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Pang, Eric, William Chong y Markham C. Luke. "Scientific and Regulatory Considerations for the Approval of the First Generic Glucagon". Journal of the Endocrine Society 5, Supplement_1 (1 de mayo de 2021): A324—A325. http://dx.doi.org/10.1210/jendso/bvab048.662.
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Abstract Glucagon for Injection (NDA 020928) is a polypeptide hormone identical to human glucagon approved 20 years ago for severe hypoglycemia in patients with diabetes mellitus. On Dec 28, 2020, the U.S. FDA approved the first generic version of glucagon for injection USP, 1 mg/vial packaged in an emergency kit. The generic and the reference listed drug (RLD) version, i.e., the innovator version, of glucagon were each produced through different manufacturing processes. The RLD version of glucagon is produced via recombinant DNA in yeast while the generic version of glucagon is produced by peptide synthesis. The FDA published its current thinking on how to ensure sameness between the generic and innovator peptide products prepared with different manufacturing processes in a Draft Guidance for Industry: Submission of Abbreviated New Drug Applications for Certain Highly Purified Synthetic Peptide Drug Products, which applies to five peptide drug products, including glucagon. In this presentation, we aim to provide an overview of the regulatory recommendations for submitting generic glucagon drug products for approval, as outlined in the aforementioned draft guidance. Although glucagon may be produced using different manufacturing processes, the sameness in glucagon can be adequately demonstrated using analytical methods, which involve demonstrating physicochemical properties, as well as primary and secondary structures, oligomers and aggregation states. Biological assays may also be used as part of the demonstration of active pharmaceutical ingredient sameness. Synthetic glucagon may have different impurity profiles when compared to the RLD recombinant product. As part of the ANDA review, impurities in the synthetic drugs are analyzed and controlled, in addition, the potential immunogenicity of new impurities, which are not in the RLD products, are assessed and compared using non-clinical assays. In this work, we will discuss non-clinical assays for assessing the immunogenicity risk of these impurities, for both adaptive and innate immune responses. In conclusion, the sameness of an approved generic synthetic glucagon to an RLD can be adequately established through various analytical methods and biological assays.
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Benet, Alexander, Troy Halseth, Jukyung Kang, April Kim, Rose Ackermann, Santhanakrishnan Srinivasan, Steven Schwendeman y Anna Schwendeman. "The Effects of pH and Excipients on Exenatide Stability in Solution". Pharmaceutics 13, n.º 8 (16 de agosto de 2021): 1263. http://dx.doi.org/10.3390/pharmaceutics13081263.
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Exenatide, a glucagon-like peptide-1 receptor agonist, is the active pharmaceutical ingredient in Byetta® and Bydureon®, two type 2 diabetes drug products that have generics and multiple follow-up formulations currently in development. Even though exenatide is known to be chemically and physically unstable at pH 7.5, there lacks a systematic evaluation of the impact of pH and excipients on the peptide solution stability. In this study, we established analytical methods to measure the chemical and physical degradation of the peptide in solution. Exenatide remained relatively stable at pH 4.5 when incubated at 37 °C. At pH 5.5–6.5, degradation was driven by oxidation, while driven by deamidation at pH 7.5–8.5. Significant aggregation of exenatide at pH 7.5 and 8.5 was detected by size exclusion chromatography and dynamic light scattering. Each pH value greater than 4.5 exhibited unique profiles corresponding to a loss of α-helical content and an increase in unordered structures. The addition of sugars, including mannitol, sorbitol and sucrose, conferred small protective effects against peptide aggregation when incubating at pH 7.5 and 37 °C, as measured by size-exclusion chromatography and dynamic light scattering. The results of this study will be useful for investigators developing generic exenatide products, peptide analogs and novel exenatide drug delivery systems.
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Kumar, K. Y. Kiran, Venugopala Rao Dama, Ch Suchitra y Thirumala Chary Maringanti. "A simple, sensitive, high-resolution, customized, reverse phase ultra-high performance liquid chromatographic method for related substances of a therapeutic peptide (bivalirudin trifluoroacetate) using the quality by design approach". Analytical Methods 12, n.º 3 (2020): 304–16. http://dx.doi.org/10.1039/c9ay01998g.
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Among all chemical sameness characterization tests of Therapeutic Peptides (TPs), one of the most significant and challenging aspects is to demonstrate comparable impurity profiles (both qualitative & quantitative) between a generic product and reference listed drug (RLD).
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Zhou, Wei, Kaylah Bias, Dylan Lenczewski-Jowers, Jiliah Henderson, Victor Cupp, Anthony Ananga, Joel Winyo Ochieng y Violeta Tsolova. "Analysis of Protein Sequence Identity, Binding Sites, and 3D Structures Identifies Eight Pollen Species and Ten Fruit Species with High Risk of Cross-Reactive Allergies". Genes 13, n.º 8 (17 de agosto de 2022): 1464. http://dx.doi.org/10.3390/genes13081464.
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Fruit allergens are proteins from fruits or pollen that cause allergy in humans, an increasing food safety concern worldwide. With the globalization of food trade and changing lifestyles and dietary habits, characterization and identification of these allergens are urgently needed to inform public awareness, diagnosis and treatment of allergies, drug design, as well as food standards and regulations. This study conducted a phylogenetic reconstruction and protein clustering among 60 fruit and pollen allergens from 19 species, and analyzed the clusters, in silico, for cross-reactivity (IgE), 3D protein structure prediction, transmembrane and signal peptides, and conserved domains and motifs. Herein, we wanted to predict the likelihood of their interaction with antibodies, as well as cross-reactivity between the many allergens derived from the same protein families, as the potential for cross-reactivity complicates the management of fruit allergies. Phylogenetic analysis classified the allergens into four clusters. The first cluster (n = 9) comprising pollen allergens showed a high risk of cross-reactivity between eight allergens, with Bet v1 conserved domain, but lacked a transmembrane helix and signal peptide. The second (n = 10) cluster similarly suggested a high risk of cross-reactivity among allergens, with Prolifin conserved domain. However, the group lacked a transmembrane helix and signal peptide. The third (n = 13) and fourth (n = 29) clusters comprised allergens with significant sequence diversity, predicted low risk of cross-reactivity, and showed both a transmembrane helix and signal peptide. These results are critical for treatment and drug design that mostly use transmembrane proteins as targets. The prediction of high risk of cross-reactivity indicates that it may be possible to design a generic drug that will be effective against the wide range of allergens. Therefore, in the past, we may have avoided the array of fruit species if one was allergic to any one member of the cluster.
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Kolstoe, Simon E. y Steve P. Wood. "Drug targets for amyloidosis". Biochemical Society Transactions 38, n.º 2 (22 de marzo de 2010): 466–70. http://dx.doi.org/10.1042/bst0380466.
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The amyloid hypothesis indicates that protein misfolding is at the root of many neurodegenerative disorders. Small molecules targeting the formation, clearance, aggregation to toxic oligomers or SOD (superoxide dismutase)-like activities of Aβ (amyloid β-peptide) 1–42 have provided encouraging candidates for AD (Alzheimer's disease) medicines in animal models, although none have yet proved to be effective in human trials. We have been investigating approaches to treat systemic amyloidoses, conditions that show common features with some CNS (central nervous system) disorders. For TTR (transthyretin) amyloidosis, we are seeking small molecule compounds that stabilize the amyloidogenic protein and either prevent its structural transition to the crossed β fibres deposited in diseased tissues, or promote its clearance from circulation. Effective stabilizer compounds that simultaneously bind to both thyroxine-binding sites have been developed. A more generic approach involves targeting the plasma glycoprotein SAP (serum amyloid P component). This protein recognizes the misfolded polypeptide structures of amyloid deposits wherever they occur, and acts as a powerful anti-opsonin. We have developed a bivalent drug called CPHPC {(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid} that cross-links pairs of pentameric SAP molecules and causes their rapid elimination from the circulation. This strategy raises the prospect of encouraging natural mechanisms to clear amyloid and recent work suggests that this approach extends to the CNS.
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Solodovnikov, A. G., E. Yu Sorokina y E. I. Morkovin. "Thrombopoietin Receptor Agonists: Clinical Use and Evaluation of Treatment Efficacy". Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products 10, n.º 4 (11 de diciembre de 2020): 236–43. http://dx.doi.org/10.30895/1991-2919-2020-10-4-236-243.
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Idiopathic thrombocytopenic purpura (ITP), or primary immune thrombocytopenia, is an orphan disease associated with thrombocytopenia. One of the most recent and promising approaches to ITP treatment is the use of thrombopoietin receptor agonists (TPO-RAs). The scope of TPO-RA use is expanding rapidly, which stimulates the development of both innovator and generic (or biosimilar) medicines. The aim of the paper was to assess TPO-RA role in ITP treatment, methodological approaches to TPO-RA development, and feasibility of using the platelet count as a pharmacodynamic marker in bioequivalence studies of peptide TPO-RAs in healthy volunteers. Clinical development of new medicines for the treatment of thrombocytopenia includes comparative, parallel-group trials lasting about a year. The standard approach to bioequivalence studies, which is based on the results of comparative pharmacokinetic studies, can be used in marketing authorisation applications for generic non-peptide TPO agonists, while peptide TPO agonists have to comply with specific requirements for biosimilar products. The orphan status of ITP does not affect the development strategy and study design, but it limits the number of patients that could be included into the study. In the absence of valid surrogate biomarkers of efficacy, demonstration of comparable clinical efficacy of the biosimilar and reference drug is usually required in a randomised, parallel, preferably double-blind comparative study. On the other hand, clinical comparability of the biosimilar and reference drug can also be demonstrated in comparative pharmacodynamic studies, if the selected biomarker is a well-established and valid surrogate marker which correlates with patient clinical outcome. Platelet count is a key parameter in both diagnosis of diseases associated with low platelet levels and assessment of treatment efficacy. Therefore, it can be used as a pharmacodynamic marker in bioequivalence studies of biosimilar peptide TPO-RAs. It was concluded that such studies could be performed in healthy volunteers, and not in patients, whose participation in clinical trials is limited due to the orphan status of ITP.
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Wang, Deyun, You Zhuo, Mike Karfunkle, Sharadrao M. Patil, Cameron J. Smith, David A. Keire y Kang Chen. "NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products". Molecules 26, n.º 14 (13 de julio de 2021): 4251. http://dx.doi.org/10.3390/molecules26144251.
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Peptide and protein drug molecules fold into higher order structures (HOS) in formulation and these folded structures are often critical for drug efficacy and safety. Generic or biosimilar drug products (DPs) need to show similar HOS to the reference product. The solution NMR spectroscopy is a non-invasive, chemically and structurally specific analytical method that is ideal for characterizing protein therapeutics in formulation. However, only limited NMR studies have been performed directly on marketed DPs and questions remain on how to quantitively define similarity. Here, NMR spectra were collected on marketed peptide and protein DPs, including calcitonin-salmon, liraglutide, teriparatide, exenatide, insulin glargine and rituximab. The 1D 1H spectral pattern readily revealed protein HOS heterogeneity, exchange and oligomerization in the different formulations. Principal component analysis (PCA) applied to two rituximab DPs showed consistent results with the previously demonstrated similarity metrics of Mahalanobis distance (DM) of 3.3. The 2D 1H-13C HSQC spectral comparison of insulin glargine DPs provided similarity metrics for chemical shift difference (Δδ) and methyl peak profile, i.e., 4 ppb for 1H, 15 ppb for 13C and 98% peaks with equivalent peak height. Finally, 2D 1H-15N sofast HMQC was demonstrated as a sensitive method for comparison of small protein HOS. The application of NMR procedures and chemometric analysis on therapeutic proteins offer quantitative similarity assessments of DPs with practically achievable similarity metrics.
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Klink, Tony A., Matt Staeben, Kim Twesten, Andrew L. Kopp, Meera Kumar, Rebecca Schall Dunn, Cori A. Pinchard, Karen M. Kleman-Leyer, Martin Klumpp y Robert G. Lowery. "Development and Validation of a Generic Fluorescent Methyltransferase Activity Assay Based on the Transcreener AMP/GMP Assay". Journal of Biomolecular Screening 17, n.º 1 (28 de septiembre de 2011): 59–70. http://dx.doi.org/10.1177/1087057111421624.
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Methylation is a ubiquitous covalent modification used to control the function of diverse biomolecules including hormones, neurotransmitters, xenobiotics, proteins, nucleic acids, and lipids. Histone methyltransferases (HMTs) are currently of high interest as drug targets because of their role in epigenetic regulation; however, most HMT assay methods are either not amenable to a high-throughput screening (HTS) environment or are applicable to a limited number of enzymes. The authors developed a generic methyltransferase assay method using fluorescent immunodetection of adenosine monophosphate (AMP), which is formed from the MT reaction product S-adenosylhomocysteine in a dual-enzyme coupling step. The detection range of the assay; its suitability for HTS, including stability of reagents following dispensing and after addition to reactions; and the potential for interference from drug-like molecules was investigated. In addition, the use of the assay for measuring inhibitor potencies with peptide or intact protein substrates was examined through pilot screening with selected reference enzymes including HMT G9a. By combining a novel enzymatic coupling step with the well-characterized Transcreener AMP/GMP assay, the authors have developed a robust HTS assay for HMTs that should be broadly applicable to other types of methyltransferases as well.
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Mallari, Rommel, Elissa Swearingen, Wei Liu, Arnold Ow, Stephen W. Young y Shu-Gui Huang. "A Generic High-Throughput Screening Assay for Kinases: Protein Kinase A as an Example". Journal of Biomolecular Screening 8, n.º 2 (abril de 2003): 198–204. http://dx.doi.org/10.1177/1087057103252306.
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A generic high-throughput screening assay based on the scintillation proximity assay technology has been developed for protein kinases. In this assay, the biotinylated 33P-peptide product is captured onto polylysine Ysi bead via avidin. The scintillation signal measuring the product formation increases linearly with avidin concentration due to effective capture of the product on the bead surface via strong coulombic interactions. This novel assay has been optimized and validated in 384-well microplates. In a pilot screen, a signal-to-noise ratio of 5-to 9-fold and a Z′ factor ranging from 0.6 to 0.8 were observed, demonstrating the suitability of this assay for high-throughput screening of random chemical libraries for kinase inhibitors. ( Journal of Biomolecular Screening 2003:198-204)
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Ummiti, Kumarswamy y J. V. Shanmukha Kumar. "Determination of Amino Acid Composition of Ganirelix Acetate in an Injectable Formulation by Pre-column Derivatization with 6-Aminoquinolyl-N-hydroxysuccinimidyl Carbamate". Journal of Chromatographic Science 58, n.º 8 (17 de julio de 2020): 687–94. http://dx.doi.org/10.1093/chromsci/bmaa030.
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Abstract Ganirelix is a synthetic decapeptide linked with nine different amino acids. To understand the peptide amino acid sequence or primary structure, the first step is to determine the amino acid composition of the peptide which can be a determining factor for the peptide immunogenicity. Edman degradation is not a suitable analytical technique to identify amino acid sequence present in Ganirelix due to the absence of uncharged N-terminal amino group. To address this challenge, a pre-column derivatization method was developed with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate reagent. In the present work, the Ganirelix active pharmaceutical ingredient present in the injectable formulation was isolated by fraction collection and further purified by flash chromatography. The amino acid composition of Ganirelix is assayed by carrying out acid hydrolysis with 6 mol L−1 hydrochloric acid solution containing 1% phenol at 100°C for 24 h and derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate reagent solution, followed by determination of individual amino acids by reverse-phase chromatography using a C18 column. High resolution was achieved for the nine amino acid mixture. The amino acid composition results of temperature-stressed Ganirelix generic product and reference listed drug are in good agreement with the theoretical molar ratio of label information.
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Pommereau, Antje, Everard Pap y Aimo Kannt. "Two Simple and Generic Antibody-Independent Kinase Assays: Comparison of a Bioluminescent and a Microfluidic Assay Format". Journal of Biomolecular Screening 9, n.º 5 (agosto de 2004): 409–16. http://dx.doi.org/10.1177/1087057104264175.
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In this study, the authors have compared the performance of 2 high-throughput screening assays for a serin/threonine kinase: a microplate-based, bioluminescent assay that uses the luciferin/luciferase system to monitor ATP consumption, and a microfluidic assay that measures the change in mobility in an electric field of a fluorescently labeled peptide upon phosphorylation. Both assays are homogeneous, nonradioactive, antibody independent and could be miniaturized to a reaction volume of 4 μl. The robustness of both formats was demonstrated by Z′ values > 0.8. Screening of a small library (2133 compounds) showed that the results obtained with both technologies correlate very well. Although the threshold for hits was set to a comparably low value—22.2% and 13.7% inhibition for the ATP consumption and microfluidic assay, respectively, corresponding to mean plus 3 standard deviations—the overlap of active compounds identified with the 2 assay formats was greater than 94%. Thus, both assays allow the identification of even low potency inhibitors with a high level of confidence.
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Perrin, Dominique, Christèle Frémaux, Dominique Besson, Wolfgang HB Sauer y Alexander Scheer. "A Microfluidics-Based Mobility Shift Assay to Discover New Tyrosine Phosphatase Inhibitors". Journal of Biomolecular Screening 11, n.º 8 (diciembre de 2006): 996–1004. http://dx.doi.org/10.1177/1087057106294094.
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Protein tyrosine phosphatases (PTPs) play key roles in regulating tyrosine phosphorylation levels in cells. Since the discovery of PTP1B as a major drug target for diabetes and obesity, PTPs have emerged as a new and promising class of signaling targets for drug development in a variety of therapeutic areas. The routine use of generic substrate 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) in our hands led to the discovery of very similar and often not very selective molecules. Therefore, to increase the chances to discover novel chemical scaffolds, a side-by-side comparison between the DiFMUP assay and a chip-based mobility shift assay with a specific phosphopeptide was performed, on 1 PTP, using a focused set of compounds. Assay robustness and sensitivity were comparable for both the DiFMUP and mobility shift assays. The off-chip mobility shift assay required a longer development time because of identification, synthesis, and characterization of a specific peptide, and its cost per point was higher. However, although most potent scaffolds found with the DiFMUP assay were confirmed in the mobility shift format, the off-chip mobility shift assay led to the identification of previously unidentified chemical scaffolds with improved druglike properties.
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Berillo, Dmitriy, Adilkhan Yeskendir, Zharylkasyn Zharkinbekov, Kamila Raziyeva y Arman Saparov. "Peptide-Based Drug Delivery Systems". Medicina 57, n.º 11 (5 de noviembre de 2021): 1209. http://dx.doi.org/10.3390/medicina57111209.
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Peptide-based drug delivery systems have many advantages when compared to synthetic systems in that they have better biocompatibility, biochemical and biophysical properties, lack of toxicity, controlled molecular weight via solid phase synthesis and purification. Lysosomes, solid lipid nanoparticles, dendrimers, polymeric micelles can be applied by intravenous administration, however they are of artificial nature and thus may induce side effects and possess lack of ability to penetrate the blood-brain barrier. An analysis of nontoxic drug delivery systems and an establishment of prospective trends in the development of drug delivery systems was needed. This review paper summarizes data, mainly from the past 5 years, devoted to the use of peptide-based carriers for delivery of various toxic drugs, mostly anticancer or drugs with limiting bioavailability. Peptide-based drug delivery platforms are utilized as peptide–drug conjugates, injectable biodegradable particles and depots for delivering small molecule pharmaceutical substances (500 Da) and therapeutic proteins. Controlled drug delivery systems that can effectively deliver anticancer and peptide-based drugs leading to accelerated recovery without significant side effects are discussed. Moreover, cell penetrating peptides and their molecular mechanisms as targeting peptides, as well as stimuli responsive (enzyme-responsive and pH-responsive) peptides and peptide-based self-assembly scaffolds are also reviewed.
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Wang, Qian, Nan Jiang, Bo Fu, Fan Huang y Jianfeng Liu. "Self-assembling peptide-based nanodrug delivery systems". Biomaterials Science 7, n.º 12 (2019): 4888–911. http://dx.doi.org/10.1039/c9bm01212e.
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The present review outlines the methods designing self-assembling peptide-based NDDs for small molecule drugs, with an emphasis on the different drug delivery strategies and their applications in using peptides and peptide conjugates.
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Wu, Qihui, Hanzhong Ke, Dongli Li, Qi Wang, Jiansong Fang y Jingwei Zhou. "Recent Progress in Machine Learning-based Prediction of Peptide Activity for Drug Discovery". Current Topics in Medicinal Chemistry 19, n.º 1 (26 de marzo de 2019): 4–16. http://dx.doi.org/10.2174/1568026619666190122151634.
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Over the past decades, peptide as a therapeutic candidate has received increasing attention in drug discovery, especially for antimicrobial peptides (AMPs), anticancer peptides (ACPs) and antiinflammatory peptides (AIPs). It is considered that the peptides can regulate various complex diseases which are previously untouchable. In recent years, the critical problem of antimicrobial resistance drives the pharmaceutical industry to look for new therapeutic agents. Compared to organic small drugs, peptide- based therapy exhibits high specificity and minimal toxicity. Thus, peptides are widely recruited in the design and discovery of new potent drugs. Currently, large-scale screening of peptide activity with traditional approaches is costly, time-consuming and labor-intensive. Hence, in silico methods, mainly machine learning approaches, for their accuracy and effectiveness, have been introduced to predict the peptide activity. In this review, we document the recent progress in machine learning-based prediction of peptides which will be of great benefit to the discovery of potential active AMPs, ACPs and AIPs.
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Kong, Xu-Dong y Christian Heinis. "Towards the Development of Orally Available Peptide Therapeutics". CHIMIA International Journal for Chemistry 75, n.º 6 (30 de junio de 2021): 514–17. http://dx.doi.org/10.2533/chimia.2021.514.
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Peptides have a number of attractive properties that make them an interesting modality for drug development, including their ability to bind challenging targets, their high target specificity, and their non-toxic metabolic products. However, a major limitation of peptides as drugs is their typically poor oral availability, hindering their convenient and flexible application as pills. Of the more than 60 approved peptide drugs, the large majority is not orally applicable. The oral delivery of peptides is hampered by their metabolic instability and/or limited intestinal uptake. In this article, we review the barriers peptides need to overcome after their oral administration to reach disease targets, we highlight two recent successes of pharma companies in developing orally applicable peptide drugs, and we discuss efforts of our laboratory towards the generation of bioavailable cyclic peptides.
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Schwardt, Oliver, Christina Lamers, Clément Bechtler y Daniel Ricklin. "Therapeutic Peptides as Emerging Options to Restore Misguided Host Defence and Homeostasis: From Teaching to Concept to Clinic". CHIMIA International Journal for Chemistry 75, n.º 6 (30 de junio de 2021): 495–99. http://dx.doi.org/10.2533/chimia.2021.495.
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Among the many molecular entities suitable for therapeutic use, peptides have emerged as a particularly attractive option for academic drug discovery and development. Their modular structure and extendibility, the availability of powerful and affordable screening platforms, and the relative ease-of-synthesis render therapeutic peptides highly approachable for teaching and research alike. With a strong focus on the therapeutic modulation of host defence pathways, including the complement and renin-angiotensin systems, the Molecular Pharmacy group at the University of Basel strongly relies on peptides to introduce students to practical aspects of modern drug design, to discover novel therapeutics for immune and inflammatory diseases, and to expand on options for the preclinical development of a promising drug class. Current projects reach from student-driven iterative design of peptidic angiotensin-converting enzyme inhibitors and the use of phage display technology to discover novel immune modulators to the development of protective peptide coatings for biomaterials and transplants and the structure-activity-relationship-guided optimization of therapeutic peptide drug candidates in late-stage clinical trials. Even at the current stage, peptides allow for a perfect circle between pharmaceutical research and education, and the recent spark of clinical applications for peptide-based drugs may only increase the value and relevance of this versatile drug class.
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He, Bifang, Canquan Mao, Beibei Ru, Hesong Han, Peng Zhou y Jian Huang. "Epitope Mapping of Metuximab on CD147 Using Phage Display and Molecular Docking". Computational and Mathematical Methods in Medicine 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/983829.
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Metuximab is the generic name of Licartin, a new drug for radioimmunotherapy of hepatocellular carcinoma. Although it is known to be a mouse monoclonal antibody against CD147, the complete epitope mediating the binding of metuximab to CD147 remains unknown. We panned the Ph.D.-12 phage display peptide library against metuximab and got six mimotopes. The following bioinformatics analysis based on mimotopes suggested that metuximab recognizes a conformational epitope composed of more than 20 residues. The residues of its epitope may include T28, V30, K36, L38, K57, F74, D77, S78, D79, D80, Q81, G83, S86, N98, Q100, L101, H102, G103, P104, V131, P132, and K191. The homology modeling of metuximab and the docking of CD147 to metuximab were also performed. Based on the top one docking model, the epitope was predicted to contain 28 residues: AGTVFTTV (23–30), I37, D45, E84, V88, EPMGTANIQLH (92–102), VPP (131–133), Q164, and K191. Almost half of the residues predicted on the basis of mimotope analysis also appear in the docking result, indicating that both results are reliable. As the predicted epitopes of metuximab largely overlap with interfaces of CD147-CD147 interactions, a structural mechanism of metuximab is proposed as blocking the formation of CD147 dimer.
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Stavchansky, Vasily V., Ivan B. Filippenkov, Julia A. Remizova, Alina E. Denisova, Ivan V. Mozgovoy, Leonid V. Gubsky, Nikolay F. Myasoedov, Lyudmila A. Andreeva, Svetlana A. Limborska y Lyudmila V. Dergunova. "Insight into Glyproline Peptides’ Activity through the Modulation of the Inflammatory and Neurosignaling Genetic Response Following Cerebral Ischemia–Reperfusion". Genes 13, n.º 12 (16 de diciembre de 2022): 2380. http://dx.doi.org/10.3390/genes13122380.
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Glyprolines are Gly-Pro (GP)- or Pro-Gly (PG)-containing biogenic peptides. These peptides can act as neutrophil chemoattractants, or atheroprotective, anticoagulant, and neuroprotective agents. The Pro-Gly-Pro (PGP) tripeptide is an active factor of resistance to the biodegradation of peptide drugs. The synthetic Semax peptide, which includes Met-Glu-His-Phe (MEHF) fragments of adrenocorticotropic hormone and the C-terminal tripeptide PGP, serves as a neuroprotective drug for the treatment of ischemic stroke. Previously, we revealed that Semax mostly prevented the disruption of the gene expression pattern 24 h after a transient middle cerebral artery occlusion (tMCAO) in a rat brain model. The genes of this pattern were grouped into an inflammatory cluster (IC) and a neurotransmitter cluster (NC). Here, using real-time RT-PCR, the effect of other PGP-containing peptides, PGP and Pro-Gly-Pro-Leu (PGPL), on the expression of a number of genes in the IC and NC was studied 24 h after tMCAO. Both the PGP and PGPL peptides showed Semax-unlike effects, predominantly without changing gene expression 24 h after tMCAO. Moreover, there were IC genes (iL1b, iL6, and Socs3) for PGP, as well as IC (iL6, Ccl3, Socs3, and Fos) and NC genes (Cplx2, Neurod6, and Ptk2b) for PGPL, that significantly changed in expression levels after peptide administration compared to Semax treatment under tMCAO conditions. Furthermore, gene enrichment analysis was carried out, and a regulatory gene network was constructed. Thus, the spectra of the common and unique effects of the PGP, PGPL, and Semax peptides under ischemia–reperfusion were distinguished.
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Ichiki, Tomoko, Atsushi Jinno y Yoshihisa Tsuji. "Natriuretic Peptide-Based Novel Therapeutics: Long Journeys of Drug Developments Optimized for Disease States". Biology 11, n.º 6 (3 de junio de 2022): 859. http://dx.doi.org/10.3390/biology11060859.
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The field of natriuretic peptides (NPs) as an endocrine hormone has been developing since 1979. There are three peptides in humans: atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), which bind to the guanylyl cyclase-A (GC-A) receptor (also called natriuretic peptide receptor-A (NPR-A)), and C-type natriuretic peptide (CNP), which binds to the GC-B receptor (also called the NPR-B) and then synthesizes intracellular cGMP. GC-A receptor stimulation has natriuretic, vasodilatory, cardiorenal protective and anti-renin–angiotensin–aldosterone system actions, and GC-B receptor stimulation can suppress myocardial fibrosis and can activate bone growth before epiphyseal plate closure. These physiological effects are useful as therapeutics for some disease states, such as heart failure, hypertension, and dwarfism. To optimize the therapeutics for each disease state, we must consider drug metabolism, delivery systems, and target receptor(s). We review the cardiac NP system; new designer NPs, such as modified/combined NPs and modified peptides that can bind to not only NP receptors but receptors for other systems; and oral drugs that enhance endogenous NP activity. Finally, we discuss prospective drug discoveries and the development of novel NP therapeutics.
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Dahiya, Sunita y Rajiv Dahiya. "BIOAVAILABILITY ENHANCEMENT AND LIPID NANOCARRIER BASED DELIVERY OF PEPTIDES AND PROTEINS". Bulletin of Pharmaceutical Research 10, n.º 1-3 (2020): 1–10. http://dx.doi.org/10.21276/bpr.2020.10.3.
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Peptides and proteins are vital biomacromolecules that perform several bodily functions in various physiological and biological processes. Being biocompatible and biodegradable, these macromolecules are considered promising platforms for delivery of drugs and genes. However, peptides and proteins suffer from major limitations including enzymatic degradation, short circulation half-lives, and poor membrane permeability that leads to poor bioavailability, challenging their effective delivery. This article briefly discusses the inherent challenges in peptide and protein delivery along with strategies for bioavailability enhancement and lipid nanocarriers as prospective systems for peptide and protein drug delivery.
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Real, Eléonore, Jean-Christophe Rain, Véronique Battaglia, Corinne Jallet, Pierre Perrin, Noël Tordo, Peggy Chrisment, Jacques D'Alayer, Pierre Legrain y Yves Jacob. "Antiviral Drug Discovery Strategy Using Combinatorial Libraries of Structurally Constrained Peptides". Journal of Virology 78, n.º 14 (15 de julio de 2004): 7410–17. http://dx.doi.org/10.1128/jvi.78.14.7410-7417.2004.
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ABSTRACT We have developed a new strategy for antiviral peptide discovery by using lyssaviruses (rabies virus and rabies-related viruses) as models. Based on the mimicry of natural bioactive peptides, two genetically encoded combinatorial peptide libraries composed of intrinsically constrained peptides (coactamers) were designed. Proteomic knowledge concerning the functional network of interactions in the lyssavirus transcription-replication complex highlights the phosphoprotein (P) as a prime target for inhibitors of viral replication. We present an integrated, sequential drug discovery process for selection of peptides with antiviral activity directed against the P. Our approach combines (i) an exhaustive two-hybrid selection of peptides binding two phylogenetically divergent lyssavirus P's, (ii) a functional analysis of protein interaction inhibition in a viral reverse genetic assay, coupled with a physical analysis of viral nucleoprotein-P complex by protein chip mass spectrometry, and (iii) an assay for inhibition of lyssavirus infection in mammalian cells. The validity of this strategy was demonstrated by the identification of four peptides exhibiting an efficient antiviral activity. Our work highlights the importance of P as a target in anti-rabies virus drug discovery. Furthermore, the screening strategy and the coactamer libraries presented in this report could be considered, respectively, a general target validation strategy and a potential source of biologically active peptides which could also help to design pharmacologically active peptide-mimicking molecules. The strategy described here is easily applicable to other pathogens.
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Yang, Yanlian y Chen Wang. "Single-molecule studies on individual peptides and peptide assemblies on surfaces". Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 371, n.º 2000 (13 de octubre de 2013): 20120311. http://dx.doi.org/10.1098/rsta.2012.0311.
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This review is intended to reflect the recent progress in single-molecule studies of individual peptides and peptide assemblies on surfaces. The structures and the mechanism of peptide assembly are discussed in detail. The contents include the following topics: structural analysis of single peptide molecules, adsorption and assembly of peptides on surfaces, folding structures of the amyloid peptides, interaction between amyloid peptides and dye or drug molecules, and modulation of peptide assemblies by small molecules. The explorations of peptide adsorption and assembly will benefit the understanding of the mechanisms for protein–protein interactions, protein–drug interactions and the pathogenesis of amyloidoses. The investigations on peptide assembly and its modulations could also provide a potential approach towards the treatment of the amyloidoses.
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Lee, Trinh, Yoo, Shin, Lee, Kim, Hwang, Lim y Ryou. "Self-Assembling Peptides and Their Application in the Treatment of Diseases". International Journal of Molecular Sciences 20, n.º 23 (21 de noviembre de 2019): 5850. http://dx.doi.org/10.3390/ijms20235850.
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Self-assembling peptides are biomedical materials with unique structures that are formed in response to various environmental conditions. Governed by their physicochemical characteristics, the peptides can form a variety of structures with greater reactivity than conventional non-biological materials. The structural divergence of self-assembling peptides allows for various functional possibilities; when assembled, they can be used as scaffolds for cell and tissue regeneration, and vehicles for drug delivery, conferring controlled release, stability, and targeting, and avoiding side effects of drugs. These peptides can also be used as drugs themselves. In this review, we describe the basic structure and characteristics of self-assembling peptides and the various factors that affect the formation of peptide-based structures. We also summarize the applications of self-assembling peptides in the treatment of various diseases, including cancer. Furthermore, the in-cell self-assembly of peptides, termed reverse self-assembly, is discussed as a novel paradigm for self-assembling peptide-based nanovehicles and nanomedicines.
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Bhargavi Ram, Thimmiah, Chien Chien Belinda Tang, Siaw Fui Kiew, Sie Yon Lau, Gobi Gobi, Jeevanandam Jaison y Michael K. Danquah. "Nanoformulation of Peptides for Pharmaceutical Applications: In Vitro and In Vivo Perspectives". Applied Sciences 12, n.º 24 (13 de diciembre de 2022): 12777. http://dx.doi.org/10.3390/app122412777.
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Peptides are short sequences of proteins consisting of two or more amino acids that are linked by peptide bonds. Peptide-based designs and drug deliveries can offer several advantages, such as antioxidant, antimicrobial, antihypertensive activities, along with immunomodulatory and antithrombotic properties, with hormone or drug-like potential. Peptide-based therapeutic formulations are used as drug candidates for the treatment of various diseases. However, there are several concerns associated with the efficacy of peptides in pharmaceutical design and delivery, including rapid degradation, limited solubility, and poor permeability. The nanoformulation of peptides has been identified as a promising approach for improving the stability of peptides and providing metabolic stability and bioavailability. This article provides an overview of the advances in the development of peptides for drug design and formulation applications. It discusses various peptide nanoformulation approaches as well as recent developments in the in vitro and in vivo analyses of nanoformulated peptides for pharmaceutical applications.
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Simper, Gwendolin S., Gia-Gia T. Hò, Alexander A. Celik, Trevor Huyton, Joachim Kuhn, Heike Kunze-Schumacher, Rainer Blasczyk y Christina Bade-Döding. "Carbamazepine-Mediated Adverse Drug Reactions: CBZ-10,11-epoxide but Not Carbamazepine Induces the Alteration of Peptides Presented by HLA-B∗15:02". Journal of Immunology Research 2018 (13 de septiembre de 2018): 1–12. http://dx.doi.org/10.1155/2018/5086503.
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Among patients treated with the anticonvulsive and psychotropic drug carbamazepine (CBZ), approximately 10% develop severe and life-threatening adverse drug reactions. These immunological conditions are resolved upon withdrawal of the medicament, suggesting that the drug does not manifest in the body in long term. The HLA allele B∗15:02 has been described to be a genomic biomarker for CBZ-mediated immune reactions. It is not well understood if the immune reactions are triggered by the original drug or by its metabolite carbamazepine-10,11-epoxide (EPX) and how the interaction between the drug and the distinct HLA molecule occurs. Genetically engineered human B-lymphoblastoid cells expressing soluble HLA-B∗15:02 molecules were treated with the drug or its metabolite. Functional pHLA complexes were purified; peptides were eluted and sequenced. Applying mass spectrometric analysis, CBZ and EPX were monitored by analyzing the heavy chain and peptide fractions separately for the presence of the drug. This method enabled the detection of the drug in a biological situation post-pHLA assembly. Both drugs were bound to the HLA-B∗15:02 heavy chain; however, solely EPX altered the peptide-binding motif of B∗15:02-restricted peptides. This observation could be explained through structural insight; EPX binds to the peptide-binding region and alters the biochemical features of the F pocket and thus the peptide motif. Understanding the nature of immunogenic interactions between CBZ and EPX with the HLA immune complex will guide towards effective and safe medications.
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Sai priya K, Raju Darla y Poojitha Gone. "Role of peptidomimetics for new drug discovery". World Journal of Advanced Research and Reviews 16, n.º 2 (30 de noviembre de 2022): 271–91. http://dx.doi.org/10.30574/wjarr.2022.16.2.1150.
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The art of transforming peptides into drug leads is still a powerful and fertile field in medicinal chemistry and drug discovery. Peptidomimetics can respond to peptide limitations by displaying higher metabolic stability, good bioavailability and increasing receptor affinity and selectivity. Various synthetic approaches and strategies have been developed over the years in order to modulate the conformational flexibility and the peptide nature of peptide mimetic compounds. This review aims to outline useful tools towards peptide mimetic design, spanning from local modifications, global restrictions and the use of secondary structure mimetics. Key learning points: Advantages of peptidomimetics over peptides, definition and classification of peptide mimetics, synthetic strategies and molecules for local modifications, secondary structure mimetics, global restrictions and Applications of peptide mimetics in drug discovery. Selected best examples of each approach are presented to document the relevance of peptidomimetics in new drug discovery.
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Yan, Evelias, Garima Goyal, Umit Hakan Yildiz, Bernhard O. Boehm y Alagappan Palaniappan. "Colorimetric Assaying of Exosomal Metabolic Biomarkers". Molecules 28, n.º 4 (16 de febrero de 2023): 1909. http://dx.doi.org/10.3390/molecules28041909.
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Exosomes released into the extracellular matrix have been reported to contain metabolic biomarkers of various diseases. These intraluminal vesicles are typically found in blood, urine, saliva, breast milk, cerebrospinal fluid, semen, amniotic fluid, and ascites. Analysis of exosomal content with specific profiles of DNA, microRNA, proteins, and lipids can mirror their cellular origin and physiological state. Therefore, exosomal cargos may reflect the physiological processes at cellular level and can potentially be used as biomarkers. Herein, we report an optical detection method for assaying exosomal biomarkers that supersedes the state-of-the-art time consuming and laborious assays such as ELISA and NTA. The proposed assay monitors the changes in optical properties of poly(3-(4-methyl-3′-thienyloxy) propyltriethylammonium bromide) upon interacting with aptamers/peptide nucleic acids in the presence or absence of target biomarkers. As a proof of concept, this study demonstrates facile assaying of microRNA, DNA, and advanced glycation end products in exosomes isolated from human plasma with detection levels of ~1.2, 0.04, and 0.35 fM/exosome, respectively. Thus, the obtained results illustrate that the proposed methodology is applicable for rapid and facile detection of generic exosomal biomarkers for facilitating diseases diagnosis.
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Boparai, Jaspreet Kaur y Pushpender Kumar Sharma. "Mini Review on Antimicrobial Peptides, Sources, Mechanism and Recent Applications". Protein & Peptide Letters 27, n.º 1 (10 de diciembre de 2019): 4–16. http://dx.doi.org/10.2174/0929866526666190822165812.
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Antimicrobial peptides in recent years have gained increased interest among scientists, health professionals and the pharmaceutical companies owing to their therapeutic potential. These are low molecular weight proteins with broad range antimicrobial and immuno modulatory activities against infectious bacteria (Gram positive and Gram negative), viruses and fungi. Inability of micro-organisms to develop resistance against most of the antimicrobial peptide has made them as an efficient product which can greatly impact the new era of antimicrobials. In addition to this these peptides also demonstrates increased efficacy, high specificity, decreased drug interaction, low toxicity, biological diversity and direct attacking properties. Pharmaceutical industries are therefore conducting appropriate clinical trials to develop these peptides as potential therapeutic drugs. More than 60 peptide drugs have already reached the market and several hundreds of novel therapeutic peptides are in preclinical and clinical development. Rational designing can be used further to modify the chemical and physical properties of existing peptides. This mini review will discuss the sources, mechanism and recent therapeutic applications of antimicrobial peptides in treatment of infectious diseases.
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Chen, Xue, Jian Huang y Bifang He. "AntiDMPpred: a web service for identifying anti-diabetic peptides". PeerJ 10 (14 de junio de 2022): e13581. http://dx.doi.org/10.7717/peerj.13581.
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Diabetes mellitus (DM) is a chronic metabolic disease that has been a major threat to human health globally, causing great economic and social adversities. The oral administration of anti-diabetic peptide drugs has become a novel route for diabetes therapy. Numerous bioactive peptides have demonstrated potential anti-diabetic properties and are promising as alternative treatment measures to prevent and manage diabetes. The computational prediction of anti-diabetic peptides can help promote peptide-based drug discovery in the process of searching newly effective therapeutic peptide agents for diabetes treatment. Here, we resorted to random forest to develop a computational model, named AntiDMPpred, for predicting anti-diabetic peptides. A benchmark dataset with 236 anti-diabetic and 236 non-anti-diabetic peptides was first constructed. Four types of sequence-derived descriptors were used to represent the peptide sequences. We then combined four machine learning methods and six feature scoring methods to select the non-redundant features, which were fed into diverse machine learning classifiers to train the models. Experimental results show that AntiDMPpred reached an accuracy of 77.12% and area under the receiver operating curve (AUCROC) of 0.8193 in the nested five-fold cross-validation, yielding a satisfactory performance and surpassing other classifiers implemented in the study. The web service is freely accessible at http://i.uestc.edu.cn/AntiDMPpred/cgi-bin/AntiDMPpred.pl. We hope AntiDMPpred could improve the discovery of anti-diabetic bioactive peptides.
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Kim, Minseon y Yongae Kim. "Structural Studies of Expressed tIK, Anti-Inflammatory Peptide". International Journal of Molecular Sciences 24, n.º 1 (30 de diciembre de 2022): 636. http://dx.doi.org/10.3390/ijms24010636.
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Cytokine imbalance is one of the causes of inflammation. Inflammation has yet to be adequately treated without side effects. Therefore, we tried to develop a peptide drug with minimal side effects. Peptide drugs have the advantage of being bio-friendly and bio-specific. In a previous study, three peptides with anti-inflammatory activity were derived based on a truncated IK (tIK) protein, which was a fragment of the IK protein with anti-inflammatory effects. The objective of this study was to optimize the process of expressing, isolating, and purifying the three peptides using bacterial strains and describe the process. Circular dichroism and solution state nuclear magnetic resonance spectroscopy were performed on the final purified high-purity peptide and its secondary structure was also identified.
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Stie, Mai Bay, Johan Ring Gätke, Ioannis S. Chronakis, Jette Jacobsen y Hanne Mørck Nielsen. "Mucoadhesive Electrospun Nanofiber-Based Hybrid System with Controlled and Unidirectional Release of Desmopressin". International Journal of Molecular Sciences 23, n.º 3 (27 de enero de 2022): 1458. http://dx.doi.org/10.3390/ijms23031458.
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The sublingual mucosa is an attractive route for drug delivery, although challenged by a continuous flow of saliva that leads to a loss of drug by swallowing. It is of great benefit that drugs absorbed across the sublingual mucosa avoid exposure to the harsh environment of the gastro-intestinal lumen; this is especially beneficial for drugs of low physicochemical stability such as therapeutic peptides. In this study, a two-layered hybrid drug delivery system was developed for the sublingual delivery of the therapeutic peptide desmopressin. It consisted of peptide-loaded mucoadhesive electrospun chitosan/polyethylene oxide-based nanofibers (mean diameter of 183 ± 20 nm) and a saliva-repelling backing film to promote unidirectional release towards the mucosa. Desmopressin was released from the nanofiber-based hybrid system (approximately 80% of the loaded peptide was released within 45 min) in a unidirectional manner in vitro. Importantly, the nanofiber–film hybrid system protected the peptide from wash-out, as demonstrated in an ex vivo flow retention model with porcine sublingual mucosal tissue. Approximately 90% of the loaded desmopressin was retained at the surface of the ex vivo porcine sublingual mucosa after 15 min of exposure to flow rates representing salivary flow.
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Liu, Yarong, Man Ji, Michael K. Wong, Kye-Il Joo y Pin Wang. "Enhanced Therapeutic Efficacy of iRGD-Conjugated Crosslinked Multilayer Liposomes for Drug Delivery". BioMed Research International 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/378380.
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Targeting nanoparticles by conjugating various specific ligands has shown potential therapeutic efficacy in nanomedicine. However, poor penetration of antitumor drugs into solid tumors remains a major obstacle. Here, we describe a targeting strategy for antitumor drug delivery by conjugating a crosslinked multilamellar liposomal vesicle (cMLV) formulation with a tumor-penetrating peptide, iRGD. The results showed that iRGD peptides could facilitate the binding and cellular uptake of drug-loaded cMLVs and consequently enhance the antitumor efficacy in breast tumor cells, including multidrug-resistant cells. Moreover, colocalization data revealed that iRGD-conjugated cMLVs (iRGD-cMLVs) entered cells via the clathrin-mediated pathway, followed by endosome-lysosome transport for efficient drug delivery. Finally,in vivostudy indicated that iRGD-cMLVs could deliver anticancer drugs efficiently to mediate significant tumor suppression.
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Vale, Nuno, Mariana Pereira, Joana Santos, Catarina Moura, Lara Marques y Diana Duarte. "Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches". International Journal of Molecular Sciences 24, n.º 1 (21 de diciembre de 2022): 69. http://dx.doi.org/10.3390/ijms24010069.
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Chemotherapy is the main treatment for most early-stage cancers; nevertheless, its efficacy is usually limited by drug resistance, toxicity, and tumor heterogeneity. Cell-penetrating peptides (CPPs) are small peptide sequences that can be used to increase the delivery rate of chemotherapeutic drugs to the tumor site, therefore contributing to overcoming these problems and enhancing the efficacy of chemotherapy. The drug combination is another promising strategy to overcome the aforementioned problems since the combined drugs can synergize through interconnected biological processes and target different pathways simultaneously. Here, we hypothesized that different peptides (P1–P4) could be used to enhance the delivery of chemotherapeutic agents into three different cancer cells (HT-29, MCF-7, and PC-3). In silico studies were performed to simulate the pharmacokinetic (PK) parameters of each peptide and antineoplastic agent to help predict synergistic interactions in vitro. These simulations predicted peptides P2–P4 to have higher bioavailability and lower Tmax, as well as the chemotherapeutic agent 5-fluorouracil (5-FU) to have enhanced permeability properties over other antineoplastic agents, with P3 having prominent accumulation in the colon. In vitro studies were then performed to evaluate the combination of each peptide with the chemotherapeutic agents as well as to assess the nature of drug interactions through the quantification of the Combination Index (CI). Our findings in MCF-7 and PC-3 cancer cells demonstrated that the combination of these peptides with paclitaxel (PTX) and doxorubicin (DOXO), respectively, is not advantageous over a single treatment with the chemotherapeutic agent. In the case of HT-29 colorectal cancer cells, the combination of P2–P4 with 5-FU resulted in synergistic cytotoxic effects, as predicted by the in silico simulations. Taken together, these findings demonstrate that these CPP6-conjugates can be used as adjuvant agents to increase the delivery of 5-FU into HT-29 colorectal cancer cells. Moreover, these results support the use of in silico approaches for the prediction of the interaction between drugs in combination therapy for cancer.
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Amorim-Carmo, Bruno, Alessandra Daniele-Silva, Adriana M. S. Parente, Allanny A. Furtado, Eneas Carvalho, Johny W. F. Oliveira, Elizabeth C. G. Santos et al. "Potent and Broad-Spectrum Antimicrobial Activity of Analogs from the Scorpion Peptide Stigmurin". International Journal of Molecular Sciences 20, n.º 3 (31 de enero de 2019): 623. http://dx.doi.org/10.3390/ijms20030623.
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Scorpion venom constitutes a rich source of biologically active compounds with high potential for therapeutic and biotechnological applications that can be used as prototypes for the design of new drugs. The aim of this study was to characterize the structural conformation, evaluate the antimicrobial activity, and gain insight into the possible action mechanism underlying it, for two new analog peptides of the scorpion peptide Stigmurin, named StigA25 and StigA31. The amino acid substitutions in the native sequence for lysine residues resulted in peptides with higher positive net charge and hydrophobicity, with an increase in the theoretical helical content. StigA25 and StigA31 showed the capacity to modify their structural conformation according to the environment, and were stable to pH and temperature variation—results similar to the native peptide. Both analog peptides demonstrated broad-spectrum antimicrobial activity in vitro, showing an effect superior to that of the native peptide, being non-hemolytic at the biologically active concentrations. Therefore, this study demonstrates the therapeutic potential of the analog peptides from Stigmurin and the promising approach of rational drug design based on scorpion venom peptide to obtain new anti-infective agents.
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Liang, Runli, Yingnan Zhang, Guangzhong Ma y Shaopeng Wang. "Charge-Sensitive Optical Detection of Binding Kinetics between Phage-Displayed Peptide Ligands and Protein Targets". Biosensors 12, n.º 6 (8 de junio de 2022): 394. http://dx.doi.org/10.3390/bios12060394.
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Phage display technology has been a powerful tool in peptide drug development. However, the supremacy of phage display-based peptide drug discovery is plagued by the follow-up process of peptides synthesis, which is costly and time consuming, but is necessary for the accurate measurement of binding kinetics in order to properly triage the best peptide leads during the affinity maturation stages. A sensitive technology is needed for directly measuring the binding kinetics of peptides on phages to reduce the time and cost of the entire process. Here, we show the capability of a charge-sensitive optical detection (CSOD) method for the direct quantification of binding kinetics of phage-displayed peptides to their target protein, using whole phages. We anticipate CSOD will contribute to streamline the process of phage display-based drug discovery.
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Cerrato, Carmine Pasquale, Tõnis Lehto y Ülo Langel. "Peptide-based vectors: recent developments". Biomolecular Concepts 5, n.º 6 (1 de diciembre de 2014): 479–88. http://dx.doi.org/10.1515/bmc-2014-0024.
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AbstractPeptides and peptide-cargo complexes have been used for drug delivery and gene therapy. One of the most used delivery vectors are cell-penetrating peptides, due to their ability to be taken up by a variety of cell types and deliver a large variety of cargoes through the cell membrane with low cytotoxicity. In vitro and in vivo studies have shown their possibility and full effectiveness to deliver oligonucleotides, plasmid DNA, small interfering RNAs, antibodies, and drugs. We report in this review some of the latest strategies for peptide-mediated delivery of nucleic acids. It focuses on peptide-based vectors for therapeutic molecules and on nucleic acid delivery. In addition, we discuss recent applications and clinical trials.
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Lee, Jong-Kook y Yoonkyung Park. "All d-Lysine Analogues of the Antimicrobial Peptide HPA3NT3-A2 Increased Serum Stability and without Drug Resistance". International Journal of Molecular Sciences 21, n.º 16 (6 de agosto de 2020): 5632. http://dx.doi.org/10.3390/ijms21165632.
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Novel antibiotic drugs are urgently needed because of the increase in drug-resistant bacteria. The use of antimicrobial peptides has been suggested to replace antibiotics as they have strong antimicrobial activity and can be extracted from living organisms such as insects, marine organisms, and mammals. HPA3NT3-A2 ([Ala1,8] HPA3NT3) is an antimicrobial peptide that is an analogue of the HP (2–20) peptide derived from Helicobacter pylori ribosomal protein L1. Although this peptide was shown to have strong antimicrobial activity against drug-resistant bacteria, it also showed lower toxicity against sheep red blood cells (RBCs) and HaCaT cells compared to HPA3NT3. The l-Lys residues of HPA3NT3-A2 was substituted with d-Lys residues (HPA3NT3-A2D; [d-Lys2,5,6,9,10,15] HPA3NT3-A2) to prevent the cleavage of peptide bonds by proteolytic enzymes under physiological conditions. This peptide showed an increased half-life and maintained its antimicrobial activity in the serum against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) (pathogen). Furthermore, the antimicrobial activity of HPA3NT3-A2D was not significantly affected in the presence of mono- or divalent ions (Na+, Mg2+, Ca2+). Finally, l- or d-HPA3NT3-A2 peptides exhibited the strongest antimicrobial activity against antibiotic-resistant bacteria and failed to induce resistance in Staphylococcus aureus after 12 passages.
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Akondi, Kalyana Bharati, Marianne Paolini-Bertrand y Oliver Hartley. "Precision-engineered Peptide and Protein Analogs: Establishing a New Discovery Platform for Potent GPCR Modulators". CHIMIA International Journal for Chemistry 75, n.º 6 (30 de junio de 2021): 489–94. http://dx.doi.org/10.2533/chimia.2021.489.
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Numerous members of the human G protein-coupled receptor (GPCR) superfamily are receptors of therapeutic interest. GPCRs are considered to be highly tractable for drug discovery, representing the targets of approximately one-third of currently licensed drugs. These successful drug discovery outcomes cover only a relatively small subset of the superfamily, however, and many other attractive receptors have proven to present significant challenges. Among these difficult GPCRs are those whose natural ligands are peptides and proteins. In this review we explain the obstacles faced by GPCR drug discovery campaigns, with particular focus on those related to peptide and protein GPCRs. We describe a novel and promising approach for these targets based on engineering of their natural ligands and describe an integrated discovery platform that allows potent ligand analogs to be discovered rapidly and efficiently. Finally, we present a case study involving the chemokine receptor CCR5 to show that this approach can be used to generate new drugs for peptide and protein GPCR targets combining best-in-class potency with tunable signaling activity.
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Jahangeer, Muhammad, Zahed Mahmood, Hira Shahid, Naveed Munir, Zahid Hussain, Areej Riasat, Shahzad Ismaeel, Usman Ali y Rehana Ramzan. "Molecular Docking and Antiviral Potential of Selected Medicinal Plants to Combat COVID-19". FRONTIERS IN CHEMICAL SCIENCES 2, n.º 1 (30 de junio de 2021): 19–43. http://dx.doi.org/10.52700/fcs.v2i1.17.
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The current emergence of the COVID-19 virus has originated a global disaster due to the unavailability of any type of vaccine or drug which can be effective and determined to combat it. Naturally, various probabilities (such as herbal remedies with known medical importance) have been investigated by scientists. Research of systematic scientific (starting from silico research) of herbal medicine in specific and any type of drug in common is now possible that is building blocks (proteins) of COVID-19 which are already being identified. Mpro or 3CLpro is the main protease of the COVID-19 virus which have an important CoV enzyme and an attractive drug target because it plays a very important role in the viral replication and transcription. By using molecular docking scientist’s aims to explore bioactive chemicals which are found in medicinal plants such as potential COVID-19 Mpro inhibitors. Molecular docking was performed by Autodock 4.2, and the Lamarckian Genetic Algorithm, for analyzing the possibility of a dock. Although, further research is needed here to investigate their uses of potential drug. And the search for new drugs, especially through the use of antiviral peptides, is a very possible and protein-protein docking were performed using silico methods to identify, test, and evaluate cell interactions and interactions of dermaseptin peptide molecules produced by Phyllomedusa frogs against SARS-CoV-2 spike protein macromolecule, with its effect on the surface attachment of the ACE-2 (Angiotensin Converting Enzyme-2) receptor. Therefore, it is hoped that the dermaseptin-S9 peptide molecule may continue to be studied in the formulation of antibodies to anti-virus peptides that will be able to control COVID-19 infectious diseases.
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Kumagai, Yuya, Yoshikatsu Miyabe, Tomoyuki Takeda, Kohsuke Adachi, Hajime Yasui y Hideki Kishimura. "In Silico Analysis of Relationship between Proteins from Plastid Genome of Red Alga Palmaria sp. (Japan) and Angiotensin I Converting Enzyme Inhibitory Peptides". Marine Drugs 17, n.º 3 (25 de marzo de 2019): 190. http://dx.doi.org/10.3390/md17030190.
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Plastid proteins are one of the main components in red algae. In order to clarify the angiotensin I converting enzyme (ACE) inhibitory peptides from red alga Palmaria sp. (Japan), we determined the plastid genome sequence. The genome possesses 205 protein coding genes, which were classified as genetic systems, ribosomal proteins, photosystems, adenosine triphosphate (ATP) synthesis, metabolism, transport, or unknown. After comparing ACE inhibitory peptides between protein sequences and a database, photosystems (177 ACE inhibitory peptides) were found to be the major source of ACE inhibitory peptides (total of 751). Photosystems consist of phycobilisomes, photosystem I, photosystem II, cytochrome complex, and a redox system. Among them, photosystem I (53) and II (51) were the major source of ACE inhibitory peptides. We found that the amino acid sequence of apcE (14) in phycobilisomes, psaA (18) and psaB (13) in photosystem I, and psbB (11) and psbC (10) in photosystem II covered a majority of bioactive peptide sequences. These results are useful for evaluating the bioactive peptides from red algae.
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Zoughaib, Mohamed, Rais V. Pavlov, Gulnara A. Gaynanova, Ruslan Garifullin, Vladimir G. Evtugyn y Timur I. Abdullin. "Amphiphilic RGD and GHK peptides synergistically enhance liposomal delivery into cancer and endothelial cells". Materials Advances 2, n.º 23 (2021): 7715–30. http://dx.doi.org/10.1039/d1ma00498k.
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Combination of RGD cell adhesion peptide with GHK cell modulator peptide synergistically improves targeting of tumor cells. Amphiphilic peptides can be effectively displayed on liposomal surface for peptide screening and drug delivery applications.
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Gatto, Emanuela, Claudio Toniolo y Mariano Venanzi. "Peptide Self-Assembled Nanostructures: From Models to Therapeutic Peptides". Nanomaterials 12, n.º 3 (28 de enero de 2022): 466. http://dx.doi.org/10.3390/nano12030466.
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Self-assembly is the most suitable approach to obtaining peptide-based materials on the nano- and mesoscopic scales. Applications span from peptide drugs for personalized therapy to light harvesting and electron conductive media for solar energy production and bioelectronics, respectively. In this study, we will discuss the self-assembly of selected model and bioactive peptides, in particular reviewing our recent work on the formation of peptide architectures of nano- and mesoscopic size in solution and on solid substrates. The hierarchical and cooperative characters of peptide self-assembly will be highlighted, focusing on the structural and dynamical properties of the peptide building blocks and on the nature of the intermolecular interactions driving the aggregation phenomena in a given environment. These results will pave the way for the understanding of the still-debated mechanism of action of an antimicrobial peptide (trichogin GA IV) and the pharmacokinetic properties of a peptide drug (semaglutide) currently in use for the therapy of type-II diabetes.
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Xiao, Yu-Feng, Meng-Meng Jie, Bo-Sheng Li, Chang-Jiang Hu, Rui Xie, Bo Tang y Shi-Ming Yang. "Peptide-Based Treatment: A Promising Cancer Therapy". Journal of Immunology Research 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/761820.
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Many new therapies are currently being used to treat cancer. Among these new methods, chemotherapy based on peptides has been of great interest due to the unique advantages of peptides, such as a low molecular weight, the ability to specifically target tumor cells, and low toxicity in normal tissues. In treating cancer, peptide-based chemotherapy can be mainly divided into three types, peptide-alone therapy, peptide vaccines, and peptide-conjugated nanomaterials. Peptide-alone therapy may specifically enhance the immune system’s response to kill tumor cells. Peptide-based vaccines have been used in advanced cancers to improve patients’ overall survival. Additionally, the combination of peptides with nanomaterials expands the therapeutic ability of peptides to treat cancer by enhancing drug delivery and sensitivity. In this review, we mainly focus on the new advances in the application of peptides in treating cancer in recent years, including diagnosis, treatment, and prognosis.
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Kaever, Thomas, Imir G. Metushi, Rebecca Pavlos, John Sidney, David A. Ostrov, Soren Buus, Alec Redwood et al. "Using MHC Binding Assays to Investigate HLA-Dependent Drug Directed Immune Responses". Journal of Immunology 198, n.º 1_Supplement (1 de mayo de 2017): 55.42. http://dx.doi.org/10.4049/jimmunol.198.supp.55.42.
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Abstract Immune mediated adverse drug reactions (IM-ADRs) pose a significant risk to human health, and have been shown to be linked to specific human leukocyte antigen (HLA) alleles. Hypersensitivity syndrome induced by abacavir, the strongest such genetic association found to date, is driven by drug-specific activation of cytokine producing, cytotoxic CD8+ T cells exclusively found in individuals expressing the HLA-B*57:01 allele variant. We have previously shown that abacavir interacts with the peptide binding cleft of the HLA-B*57:01 molecule, thus increasing the affinity of certain self-peptides generating an altered self-peptide repertoire. In MHC binding studies a second drug, acyclovir, also revealed a dose dependent increase in affinity for peptides that contain small, hydrophobic residues at the C terminus. Peptide elution studies performed in the presence of acyclovir showed an elevated number of endogenously bound peptides with a C-terminal isoleucine. Accordingly, we concluded that acyclovir acts by the same mechanism as abacavir, albeit at a lesser magnitude. Our data showed a maximum increase of affinity of 2.5-fold for acyclovir, when the effect of abacavir was as high as 1000-fold. Acyclovir is not known to cause IM-ADRs. We concluded that the moderate effect of acyclovir on binding affinity was not sufficient to cause a hypersensitivity reaction. Here we applied the same screening strategies to four compounds that are involved in IM-ADRs with strong known HLA association, to determine if drug specific effects of these molecules could be observed. While no effect as striking as that for abacavir could be detected, several notable changes in repertoire were associated with the presence of these compounds.
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Stephanie, Filia, Mutiara Saragih, Usman Sumo Friend Tambunan y Teruna J. Siahaan. "Structural Design and Synthesis of Novel Cyclic Peptide Inhibitors Targeting Mycobacterium tuberculosis Transcription". Life 12, n.º 9 (28 de agosto de 2022): 1333. http://dx.doi.org/10.3390/life12091333.
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Tuberculosis (TB) remains one of the deadliest infectious diseases in the world. Although several established antitubercular drugs have been found, various factors obstruct efforts to combat this disease due to the existence of drug-resistance (DR) TB strains, the need for lengthy treatment, and the occurrence of side effects from drug–drug interactions. Rifampicin (RIF) is the first line of antitubercular drugs and targets RNA polymerase (RNAP) of Mycobacterium tuberculosis (MTB). Here, RIF blocks the synthesis of long RNA during transcription initiation. The efficacy of RIF is low in DR-TB strains, and the use of RIF leads to various side effects. In this study, novel cyclic peptides were computationally designed as inhibitors of MTB transcription initiation. The designed cyclic peptides were subjected to a virtual screening to generate compounds that can bind to the RIF binding site in MTB RNAP subunit β (RpoB) for obtaining a new potential TB drug with a safe clinical profile. The molecular simulations showed that the cyclic peptides were capable of binding with RpoB mutants, suggesting that they can be possibility utilized for treating DR-TB. Structural modifications were carried out by acetylation and amidation of the N- and C-terminus, respectively, to improve their plasma stability and bioavailability. The modified linear and cyclic peptides were successfully synthesized with a solid-phase peptide synthesis method using Fmoc chemistry, and they were characterized by analytical HPLC, LC-ESI-MS+, and 1H NMR.
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La Manna, Sara, Concetta Di Natale, Valentina Onesto y Daniela Marasco. "Self-Assembling Peptides: From Design to Biomedical Applications". International Journal of Molecular Sciences 22, n.º 23 (23 de noviembre de 2021): 12662. http://dx.doi.org/10.3390/ijms222312662.
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Self-assembling peptides could be considered a novel class of agents able to harvest an array of micro/nanostructures that are highly attractive in the biomedical field. By modifying their amino acid composition, it is possible to mime several biological functions; when assembled in micro/nanostructures, they can be used for a variety of purposes such as tissue regeneration and engineering or drug delivery to improve drug release and/or stability and to reduce side effects. Other significant advantages of self-assembled peptides involve their biocompatibility and their ability to efficiently target molecular recognition sites. Due to their intrinsic characteristics, self-assembled peptide micro/nanostructures are capable to load both hydrophobic and hydrophilic drugs, and they are suitable to achieve a triggered drug delivery at disease sites by inserting in their structure’s stimuli-responsive moieties. The focus of this review was to summarize the most recent and significant studies on self-assembled peptides with an emphasis on their application in the biomedical field.
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Li, Caroline M., Pouya Haratipour, Robert G. Lingeman, J. Jefferson P. Perry, Long Gu, Robert J. Hickey y Linda H. Malkas. "Novel Peptide Therapeutic Approaches for Cancer Treatment". Cells 10, n.º 11 (27 de octubre de 2021): 2908. http://dx.doi.org/10.3390/cells10112908.
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Peptides are increasingly being developed for use as therapeutics to treat many ailments, including cancer. Therapeutic peptides have the advantages of target specificity and low toxicity. The anticancer effects of a peptide can be the direct result of the peptide binding its intended target, or the peptide may be conjugated to a chemotherapy drug or radionuclide and used to target the agent to cancer cells. Peptides can be targeted to proteins on the cell surface, where the peptide–protein interaction can initiate internalization of the complex, or the peptide can be designed to directly cross the cell membrane. Peptides can induce cell death by numerous mechanisms including membrane disruption and subsequent necrosis, apoptosis, tumor angiogenesis inhibition, immune regulation, disruption of cell signaling pathways, cell cycle regulation, DNA repair pathways, or cell death pathways. Although using peptides as therapeutics has many advantages, peptides have the disadvantage of being easily degraded by proteases once administered and, depending on the mode of administration, often have difficulty being adsorbed into the blood stream. In this review, we discuss strategies recently developed to overcome these obstacles of peptide delivery and bioavailability. In addition, we present many examples of peptides developed to fight cancer.
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Tailor, Arun, Xiaoli Meng, Kareena Adair, John Farrell, James C. Waddington, Ann Daly, Munir Pirmohamed, Gordon Dear, B. Kevin Park y Dean J. Naisbitt. "HLA DRB1*15:01-DQB1*06:02-Restricted Human CD4+ T Cells Are Selectively Activated With Amoxicillin-Peptide Adducts". Toxicological Sciences 178, n.º 1 (10 de agosto de 2020): 115–26. http://dx.doi.org/10.1093/toxsci/kfaa128.
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Abstract Amoxicillin-clavulanate is the most common cause of idiosyncratic drug-induced liver injury (DILI). Drug-specific CD4+ T cells have been detected in patients with DILI, suggestive of an immune etiology. Furthermore, genetic associations including the human leucocyte antigen (HLA) DRB1*15:01-DQB1*06:02 haplotype influence susceptibility. Amoxicillin forms protein adducts that are postulated to activate T cells, by conjugating with lysine residues. However, a role for such adducts has not been described. This study aimed to (1) investigate whether amoxicillin-modified HLA-DRB1*15:01-DQB1*06:02 binding peptides selectively activate DILI patient T cells and (2) define the nature of the T-cell response with respective to antigen structure. Peptides carrying lysine residues for amoxicillin binding in positions (KP) 2-6 and anchors for the HLA-DRB1*15:01-DQB1*06:02 haplotype were designed. The amoxicillin-modified peptides were characterized by mass spectrometry prior to culturing with patient peripheral blood mononuclear cell. T-cell clones were then tested for specificity with amoxicillin, unmodified- and amoxicillin-modified peptides, and structural variants. Amoxicillin-modified KP-2 and KP-3 peptide-specific CD4+ clones proliferated and secreted interferon gamma (IFN-γ), interleukin (IL)-10, perforin and/or IL-17/IL-22 in a dose-dependent manner and displayed no cross-reactivity with amoxicillin, unmodified peptide or with positional derivatives. The T cells response was HLA class II restricted and the amoxicillin-modified peptides bound selectively to HLA-DRB1*15:01 and/or DQB1*06:02. To conclude, we show that amoxicillin-modified peptides bind to both components of the risk haplotype to stimulate DILI patient T cells and describe the importance of the position of nucleophilic lysine residue in the HLA binding peptide sequence.
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Heh, Ethan, Jesse Allen, Fabiola Ramirez, Daniel Lovasz, Lorena Fernandez, Tanis Hogg, Hannah Riva, Nathan Holland y Jessica Chacon. "Peptide Drug Conjugates and Their Role in Cancer Therapy". International Journal of Molecular Sciences 24, n.º 1 (3 de enero de 2023): 829. http://dx.doi.org/10.3390/ijms24010829.
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Drug conjugates have become a significant focus of research in the field of targeted medicine for cancer treatments. Peptide-drug conjugates (PDCs), a subset of drug conjugates, are composed of carrier peptides ranging from 5 to 30 amino acid residues, toxic payloads, and linkers that connect the payload to the peptide. PDCs are further broken down into cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs), each having their own differences in the delivery of cytotoxic payloads. Generally, PDCs as compared to other drug conjugates—like antibody-drug conjugates (ADCs)—have advantages in tumor penetration, ease of synthesis and cost, and reduced off-target effects. Further, as compared to traditional cancer treatments (e.g., chemotherapy and radiation), PDCs have higher specificity for the target cancer with generally less toxic side effects in smaller doses. However, PDCs can have disadvantages such as poor stability and rapid renal clearance due to their smaller size and limited oral bioavailability due to digestion of its peptide structure. Some of these challenges can be overcome with modifications, and despite drawbacks, the intrinsic small size of PDCs with high target specificity still makes them an attractive area of research for cancer treatments.