Littérature scientifique sur le sujet « Generic peptide drug »
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Articles de revues sur le sujet "Generic peptide drug"
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Pang, Eric, William Chong et Markham C. Luke. « Scientific and Regulatory Considerations for the Approval of the First Generic Glucagon ». Journal of the Endocrine Society 5, Supplement_1 (1 mai 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ensure sameness between the generic and innovator peptide products prepared with different manufacturing processes in a Draft Guidance for Industry: Submission of Abbreviated New Drug Applications for Certain Highly Purified Synthetic Peptide Drug Products, which applies to five peptide drug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recommendations for submitting generic glucagon drug products for approval, as outlined in the aforementioned draft guidance.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 et Anna Schwendeman. « The Effects of pH and Excipients on Exenatide Stability in Solution ». Pharmaceutics 13, no 8 (16 août 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 et 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, no 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 et 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, no 8 (17 août 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., et Steve P. Wood. « Drug targets for amyloidosis ». Biochemical Society Transactions 38, no 2 (22 mars 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 et 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, no 4 (11 décembre 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 et Kang Chen. « NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products ». Molecules 26, no 14 (13 juillet 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 et 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, no 1 (28 septembre 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 et Shu-Gui Huang. « A Generic High-Throughput Screening Assay for Kinases : Protein Kinase A as an Example ». Journal of Biomolecular Screening 8, no 2 (avril 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, et 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, no 8 (17 juillet 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.
Thèses sur le sujet "Generic peptide drug"
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Johansen-Leete, Jason Paul. « Discovery of Bioactive macrocyclic peptides using mRNA display with genetic reprogramming ». Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/29467.
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Macrocyclic peptides are attractive for their favourable drug-like properties, bridging the gap between small molecules and biologics. Whilst nature is a rich source of bioactive macrocyclic peptides, their de novo discovery would access the full potential of this chemotype for therapeutic use. Using its ultra-large libraries of >1012 unique peptides, mRNA display is a powerful method of de novo ligand discovery against protein target. Genetic reprogramming can be exploited to display peptides with modified structures to improve their drug-like properties, such as affinity and cell-permeability.
Chapter 2 describes the first reprogramming of sulfotyrosine into mRNA display for the discovery of chemokine-binding cyclic peptides, discovering several high-affinity sulfated ligands which inhibited chemotactic signalling. Chapter 3 provides an overview of COVID-19 proteases. Replication of SARS-CoV-2 uses two viral proteases, the papain-like protease (PLpro) and the main protease (Mpro), and are of extreme interest as antiviral drug targets for COVID-19. Chapter 4 describes the discovery macrocyclic inhibitors of SARS-CoV-2 PLpro. Initially discovering peptide binders to PLpro with modest inhibitory activity against the protease, we hypothesised leveraging genetic code reprogramming to discover covalent inhibitors would generate higher affinity PLpro ligands. After panning several covalent warhead-containing amino acids, we identified a cysteine-reactive methylacrylamide-moeity compatible with ribosomal incorporation. This lays the foundation for the future discovery of covalent cyclic peptide inhibitors of PLpro and other cysteine proteases. Chapter 5 describes genetically reprogrammed mRNA display to discover several potent inhibitors of the SARS-CoV-2 Mpro which also exhibited in vitro antiviral activity. The novel antiviral molecules discovered in this work exemplify the power of the cyclic peptide chemotype and the need for its further development.
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Sen, Gulseren Petek. « Fabrication Of Poly (dl-lactic-co-glycolic Acid) Nanoparticles And Synthetic Peptide Drug Conjugate For Anti-cancer Drug Delivery ». Master's thesis, METU, 2010. http://etd.lib.metu.edu.tr/upload/12611405/index.pdf.
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Cancer is a group of diseases in which normal cells are converted to cells capable of autonomous growth and invasion. In the chemotherapeutic control of cancer, drugs are usually given systemically so they reach toxic levels in healthy cells as well as cancer cells. This causes serious side effects. Another important problem with chemotherapy is resistance developed to cytotoxic drugs (multi drug resistance).
Doxorubicin (Dox) occupies a central position in the treatment of breast cancer. However doxorubicin induced cardiac toxicity is associated with a high incidence of morbidity and mortality. Resistance of malignant tumors to Dox is another important cause of treatment failure in patients with cancer.
One approach to overcome Dox-related toxicity is to use polymeric drug carriers, which direct the Dox away from heart tissue, and allow usage of lower dosages. In this present study two different anti-cancer drug delivery methods were evaluated. Dox was encapsulated in PLGA microparticles by single and double microemulsion solvent evaporation techniques. The highest entrapment of doxorubicin within PLGA microspheres obtained by optimization of process parameters. A sustained release of doxorubicin was obtained for 20 days.
Several protein transduction domains are known to have the ability to pass through biological membranes. One such peptide is HIV-1 TAT. In this study TAT was evaluated for its ability to carry Dox into Dox resistant MCF-7 tumor cells. Dox peptide conjugate was more potent than free drug. The concentration of drug in resistant cancer cells was increased indicating a partial reversal of drug resistance.
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Cai, Minying. « Exploring the stereostructural requirements of peptide ligands for the melanocortin receptors and molecular mechanism study of GPCR based drugs ». Diss., The University of Arizona, 2004. http://hdl.handle.net/10150/280591.
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A central goal of modern biology is to develop a detailed, predictive understanding of the relationships of three-dimensional structure and biological function. We are attempting build this relationship by combining interdisciplinary work. The dissertation is divided into two parts. In the first part of work, numerous structure-activitiy relationships (SAR) studies of different conformationally constrained peptides and peptide mimetics of human melanotropins have been accomplished and discussed. Through this very tedious hard work, selective agonists and antagonists for each subtype of melanocortin receptors have been obtained. We first started investigating the NMR 3D pharmacophore of agonist and antagonist of human melanotropin based on the NMR structure of AGRP ( PDB: 1HYK) and MTII. After a long struggle with appropriate force fields and calculation methodologies, almost identical structures were obtained for MTII as well as SHU-9119 by employing two different techniques of LLMOD (Large scale Lower Modes of Modeling) and NMR. Combining the existing SAR data with this new modeling approach, a series of linear and cyclized peptides (hybridization of the pharmacophore of AGRP and MTII) have been designed, synthesized and identified. We have been successful in obtaining selective agonists and antagonists of melanocortin receptors and these new discoveries shed new insight into peptide or nonpeptide selective drug design for the future. The second part of the dissertation mainly covers human melanocortin receptor (hMCRs) studies. For the purpose of screening the novel peptides and nonpeptides of melanotropins, a series of human melanocortin receptors have been stably transfected into HEK 293 cell line, and new high throughput screening methodologies have been set up. For the purpose of purification of the melanocortin receptors, hMC4R and hMC1R, -His-tag-flag stably transfected into HEK293 cell lines have been designed and applied in receptor purification. We also further studied the mechanism of selective pathway of melanotropin in the HEK293 cells. It was found that agonist mediated internalization of all subtypes of melanocortin receptors are dependent upon beta-arrestin mediated clathrin coated pits, and on the contrary, beta-Arrestin2-GFP recruitment is not dependent on PKA activation. The two-photon fluorescence laser scanning microscopy is a fast, powerful method to study the molecular mechanisms of G protein coupled receptor regulation. In addition, this technique also can serve as a rapid, real-time screening method to differentiate between agonists and antagonists irrespective of any knowledge of their intracellular functional properties (orphan receptors).
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Ahlin, Gustav. « In vitro and in silico prediction of drug-drug interactions with transport proteins ». Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-107492.
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Calmann, Melissa A. « The Roles of DNA Mismatch Repair and Recombination in Drug Resistance : A Dissertation ». eScholarship@UMMS, 2004. https://escholarship.umassmed.edu/gsbs_diss/109.
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Cells have evolved different pathways in order to tolerate damage produced by different cytotoxic agents. Each agent reacts differently with DNA causing formation of different types of adducts, each eliciting the SOS stress response to induce different cellular repair pathways. One such type of substrate generated by cytotoxic agents is the DNA double strand break (DSB). The main pathway to repair such damage in the cell is through a process of recombination. In this thesis, I specifically examined the anti-cancer therapeutic agent cisplatin, which forms single- and double-strand breaks in DNA, and methylating agents, which are proposed to also be capable of forming such breaks. Neither type of agent can directly form these breaks; however, they leave a signature type of damage lesion which is recognized by different repair processes.
The mismatch repair (MMR) status of a mammalian cell or an Escherichia coli dam mutant relates directly to the sensitivity of the cells to the agents mentioned above. As the dam gene product plays an important role in this pathway and in other processes in the cell, when mutated, dam cells are more sensitive to methylating agents and cisplatin than wildtype. A combination of dam and either mutS or mutL restores resistance to the same agents to wild type levels. Therefore, mismatch repair sensitizes dam bacteria to these agents. The rationale for this comes from examining the viability of dam mutants, as dammutants are only viable because they are highly recombinogenic. The presence of MMR-induced nicks or gaps results in the formation of DSBs that require recombination to restore genomic integrity.
Mismatch repair proteins inhibit recombination between homeologous DNA. Homeologous recombination (recombination between non-identical, but similar, DNA sequences) is only possible when the MMR proteins, MutS and MutL, are absent. It is postulated that this is because MutS recognizes the homeologous DNA and subsequently slows down or aborts recombination completely. The double mutant, dam mutS/L shows wild type levels of sensitivity to cisplatin because mismatch repair is no longer recognizing the adducts and recombinational repair is allowed to continue. Human cells behave in an analogous fashion to the bacterial dam mutant, showing sensitivity to cisplatin and methylating agents. When an additional mutation in a mismatch repair gene is present, the cells become as resistant as wild type. Therefore, the E. coli dammutant is a useful model system to study this mechanism of drug resistance.
DNA containing cisplatin adducts or lesions resulting from methylation are substrates for other types of repair processes such as nucleotide excision repair and base excision repair; however they have also been implicated as substrates for MMR and recombinational repair. The goal of the work in this thesis was two-fold. The first was to identify the gene products and mechanism necessary for repair of cisplatin damage by recombination. The second was to examine the mechanism of cisplatin toxicity, and specifically how MMR proficiency aids in the cytotoxicity of this drug by preventing recombination.
Using the duplicated inactive lac operon recombination assay, we were able to determine the requirements for spontaneous and cisplatin-induced recombination, the RecBCD and RecFOR pathways. We were also able to further postulate that the cisplatin- induced signature damage recognized by recombination was the double strand break, likely formed from fork stalling and regression or a subsequent collapse during DNA synthesis, thus requiring these pathways for repair. This observation led to the experiments involving examination of the mechanism of cisplatin toxicity and where MMR could inhibit specific steps of recombination with DNA containing cisplatin lesions. Low levels of cisplatin lesions slowed the rate of RecA-mediated strand transfer in vitro, likely due to its ability to form a large bend in the DNA. MutS bound to cisplatin lesions in the DNA during heteroduplex formation in the RecA strand exchange step of recombination, inhibiting branch migration, and aborting the reaction. In order for MutS to inhibit recombination with cisplatin lesions, the results in the work in Chapter IV, show that binding to the lesion requires the C-terminus of MutS to be present, possibly due to a requirement for tetramerization of the protein, a domain contained in the C-terminus of MutS. This antirecombination function is different than the mutation avoidance function of MutS, as binding of mismatches requires only dimers. This differential sensitivity for cisplatin versus a mismatch was further exemplified in Chapter V, the experiments with dna mutants, where the greatest difference in sensitivity was observed for a dnaE mutant (catalytic subunit of polIII), which was as sensitive to cisplatin as a dam mutant, but fairly resistant to treatment with MNNG. This is indicative of the potency of a cisplatin adduct to block polymerase progression, versus a mismatch which poses little problem to synthesis. Recombination is invoked to repair DSBs caused by the cisplatin lesions through the RecBCD and FOR pathways after fork regression or collapse. A main conclusion from these studies is that a cisplatin lesion is processed differently than a mismatch. The mechanism of how a cisplatin lesion is processed, forming the DSB which invokes recombinational repair is still unclear and continues to be investigated.
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Schroeder, Frederick Albert. « A Role for Histone Modification in the Mechanism of Action of Antidepressant and Stimulant Drugs : a Dissertation ». eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/370.
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Depression and stimulant drug addiction each result in massive losses of health, productivity and human lives every year. Despite decades of research, current treatment regimes for depression are ineffective in approximately half of all patients. Therapy available to stimulant drug addicts is largely ineffective and moreover, dedicated treatments for drug dependence (including abuse of cocaine) are non-existent. Thus, there is a pressing need to further understanding of the molecular mechanisms underlying these disorders in order to develop novel, targeted therapeutic strategies.
Chromatin remodeling, including changes in histone acetylation, has been proposed to play a role in both the etiology and treatment of depression and stimulant abuse. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate numerous cellular processes, including transcription, cell cycle progression and differentiation. Moreover, histone acetylation has been shown to regulate hippocampal neurogenesis, a cellular response associated with the pathogenesis and treatment of depression and stimulant abuse (Hsieh et al., 2004, Yamaguchi et al., 2004, Fischer et al., 2007). Ultimately, such basic cellular processes impact higher order function, namely cognition and emotion.
Indeed, recent studies suggest that HDAC activity in selected forebrain regions, including ventral striatum and hippocampus, modulate stimulant- and antidepressantinduced behavior (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). These reports highlight an association between chromatin remodeling and diverse behavioral changes, including changes induced by the pleiotropic HDAC inhibitor, sodium butyrate (SB), (Kumar et al., 2005, Tsankova et al., 2006a, Fischer et al., 2007). However, behavioral, brain-metabolic and molecular effects of SB treatment in the context of rodent models of depression, dopaminergic sensitization and repeated cocaine administration remained unclear.
The work described in this thesis illustrates the potential for chromatin modifying drugs in mechanisms underlying the experimental pharmacology of depression and stimulant addiction. Specifically, the data presented here support the view that treatment with the short chain fatty acid, sodium butyrate enhances: (1) antidepressant-like behavioral effects of the selective serotonin reuptake inhibitor (SSRI), fluoxetine (2) locomotor sensitization induced by repeated administration of the dopamine D1/D5 receptor agonist SKF82958; and(3) brain metabolic activation upon repeated cocaine administration as evidenced by fMRI in awake rats.
Furthermore, this report provides evidence that these treatment paradigms will result in chromatin modification changes associated with active transcription, in addition to increased mRNA levels of plasticity-associated genes, including brain-derived neurotrophic factor (BDNF) at key brain regions implicated in the pathogenesis of depression and stimulant addiction.
To date, little is known regarding the underlying mechanisms of action mediating the enhancing effects of sodium butyrate on the various antidepressant- and stimulantrelated paradigms. Our findings underscore the potential of chromatin-modifying drugs to profoundly affect the behavioral response of an animal to antidepressant and stimulant drugs and warrants consideration in the context of developing novel therapeutic strategies.
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Stennett, Bethany Ann. « Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats ». UNF Digital Commons, 2013. http://digitalcommons.unf.edu/etd/465.
Texte intégralRésumé :
The co-dependence of nicotine and alcohol addiction occurs at high rates, complicates treatment, and is often associated with significant morbidity and mortality. Treatment options of alcohol and tobacco co-dependence are limited. Currently, there are drugs available for nicotine dependence or alcohol dependence. However, there are no therapeutic drugs available on the market for the co-dependence of nicotine and alcohol. Therefore, and important opportunity of new therapeutic options and drug development has presented itself. NT69L, a non-selective neurotensin (NT) agonist, provides a potential novel therapy for nicotine addiction in alcoholics by interacting with the common neurotransmitter circuits supporting the rewarding process for both nicotine and alcohol. Considering the behavioral effects of NT69L in attenuating nicotine self-administration in rats and alcohol consumption in mice, the present study was designed to assess the effects of NT69L as a new drug. NT69L was used in the treatment of nicotine addiction in an animal model of alcoholics and in attempts to attenuate withdrawal signs associated with nicotine and alcohol dependence. Wistar rats pre-exposed to alcohol vapor or air were allowed to self-infuse nicotine (0.03mg/kg/infusion) or saline. When the rats reached a stable level of responding, the effect of pretreatment with NT69L (1mg/kg i.p.) on the reinforcing effect of nicotine was determined. Animals self-infused nicotine at a significantly (p < .05) higher rate compared to saline in both air and alcohol vapor exposed groups. Acute pretreatment with a single injection of NT69L significantly (p < .05) reduced nicotine self-infusion in both the alcohol vapor and the air exposed groups for 5 days post-injection. Additionally, NT69L attenuated the alcohol- and nicotine-induced withdrawal signs associated with the discontinuation of alcohol and nicotine administration. Neurotensin agonist, NT69L, may represent a potential novel therapy to treat the co-addiction of alcohol and nicotine.
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D'Ercole, Annunziata. « Development and scale-up of synthetic strategies for exotic macrocyclisation to increase druggability of peptides as active pharmaceutical ingredients of industrial interest ». Doctoral thesis, 2022. http://hdl.handle.net/2158/1264636.
Texte intégralRésumé :
In the framework of the PhD project of industrial interest, I have been involved
in the development and optimization of synthetic procedures to obtain peptides of
pharmaceutical interest, both on the laboratory scale and for the industrial
production, in the context of the University-Industry Joint Laboratory PeptFarm
of the University of Florence.
This research develops through two parallel lines. The former is related to the
development of a multigram, scalable cGMP-compliant MW-SP synthetic
approach for the manufacture of the cyclic peptide Active Pharmaceutical
Ingredient Eptifibatide acetate. Additionally, an alternative, patentable synthetic
approach has been developed to overcome patent restrictions.
On the other hand, the development of an efficient synthetic strategy for the
preparation of a library of stapled peptides of pre-clinical interest derived from
relaxin hormone was performed, aiming to investigate their biological role.
Moreover, the feasibility of an oral administration of serelaxin gastroprotected
formulations were investigated.
According to the industrial perspective on research needs and opportunities in
manufacturing, automation of as many steps as possible within an industrial
production frame is pivotal to guarantee safety requirements. Solid-phase
strategies are considered methods of election for medium-length peptide
syntheses not only at the research scale but for large-scale production, as well.
The possibility to use microwave-assisted technology on the large scale recently
introduced, prompted us to evaluate the possibility to conveniently set-up a safe
and fully cGMP-compliant pilot process to produce Eptifibatide acetate Active
Pharmaceutical Ingredients (API), a generic hexapeptide, characterized by a
single disulfide bridge. We investigated strategies based on the use of the
microwave-assisted solid-phase peptide synthesis (MW-SPPS), by the use of a
DIC/Oxyma Pure coupling protocol at 90 °C. This fully automated technology,
previously accessible only at R&D level, has been recently made available also
for the large-scale manufacturing of peptide APIs, taking constantly into account
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the cost-effectiveness and dangerousness of each procedure. Accordingly, we
developed an optimized process at the laboratory scale (1-5 mmol), which was
subsequently successfully scaled-up to 70 mmol, obtaining all the information
required by regulatory agencies to validate the process and qualify the pilot-scale
plant. The process consists of 5 steps: 1) automated microwave-assisted solid phase
synthesis of Eptifibatide linear precursor; 2) cleavage from the resin with
concomitant amino acid side-chains deprotection; 3) disulfide-bond formation in
solution; 4) purification by flash column chromatography; 5) ion-exchange solid phase
extraction. Since the direct scale-up of a kg-scale, cGMP compliant
peptide API production procedure is a challenge that requires an accurate
understanding of each involved step, we preliminary performed a quality
management risk assessment, which enabled a smooth and effective achievement
of a successful final result. Moreover, in our optimization process, a reduction in
time, solvents and waste have been obtained, ensuring compliance with the
quality specifications, according to regulatory agencies requirements (FDA and
EMA). Satisfactory results were obtained in terms of Eptifibatide acetate HPLC
purity (99.6%) and Yield (22.1%).
Additionally, the investigation of an alternative on-resin cyclization strategy for
therapeutic peptide industrial production of Eptifibatide acetate has been carried
out in parallel with the aim to develop a robust and economically competitive
production process avoiding intermediate steps of isolation to preserve the
recovery guaranteeing a GMPs quality product, to overcome patent restrictions.
A scalable, fully automated approach performed entirely in the same reactor has
been developed. We explored and compared four solid-phase disulfide formation
approaches (A, B, C, D) between the C-terminal Cys and the N-terminal 3-
Mercaptopropionic acid (MPA). These mainly differ one from each other for the
final cyclization step, obtained by direct formation of an S-S disulfide bridge
(strategies A-B) or via side-chain-to-tail amide bond formation (strategies C-D).
Strategy D resulted the best one, thanks to the concomitant reduction of the Stert-
butylthio (StBu) Cys protecting group (PG) and disulfide formation with the
MPA reducing agent, enjoying the advantage of using an already qualified
starting material. This strategy (D) represents an inventive (non-obvious)
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strategy, (since we were the first to propose MPA to deprotect StBu on cysteine),
which proposes for the first time to perform all the processes including disulfide
bond formation in a single reactor (novelty), scalable on multigram-scale by
Liberty Pro synthesizer (Industrial applicability). Therefore, according to the
three patentability criteria required for a new production process: Novelty;
inventive and industrial applicability, the present PhD work identifies a new
patentable production process.1
In line with the synthesis of conformationally constraint relaxin derivatives, the
present work describes the development of an innovative, efficient and
reproducible MW-assisted Copper-Catalyzed Azide-Alkyne Cycloaddition (SP
MW-CuAAC) performed on solid phase to prepare side-chain-to-side-chain
clicked H1-relaxin single B-chain analogues, overcoming the several synthetic
drawbacks (aggregation tendency and poor solubility) which hamper
relaxins syntheses.
All the relevant parameters, that are, resin (PEG-PS vs PS), solvent mixtures
(H2O:t-BuOH:DCM 1:1:1, DMSO:DMF 1:2), catalytic system (CuBr vs CuSO4),
microwave energy and reaction time were optimized using a systematic
approach.2 Two generations of H1-relaxin single B-chain stapled analogues were
obtained. First-generation (VR and VIR) and second-generation H1-relaxin
single B-chain peptides (VII and VIIR; VIII and VIIIR; IX and IXR) were
characterized by different lengths and different positions and orientations of the
triazolyl ring, and were designed with the aim to stabilize the α-helix
conformation and to expose the binding cassette motif. The α-helicity induced by
the side-chain to side-chain stapling obtained was demonstrated by the circular
dichroism (CD) performed both in phosphate buffer and in SDS micelle, thanks
to the collaboration with Prof. A. Carotenuto (University of Naples Federico II).
Moreover, in the frame of the collaboration with Prof. D. Bani (University of
Florence) and Prof. A. Hossein (Institute of Neuroscience and Mental Health,
University of Melbourne, Australia), H1-relaxin analogues were biologically
tested, to verify binding to cells expressing the receptor RXFP1 and activity
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through cAMP signaling pathway in HEK-293T cells stably expressing the
RXFP1 receptor.
Moreover, since the major challenge in the development of peptide drugs is to
improve their oral bioavailability, we investigated the relative bio-potency of the
intact serelaxin molecule (the recombinant form of human H2-relaxin) and the
purified porcine one, in comparison with their proteolytic fragments, obtained
after treatment with Simulated Intestinal Digestion Fluid (SIF). Signalling events
downstream receptor activation in THP-1 human monocytic cells was measured.
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Mukkamala, Venkata C. S. Dushyant. « NMR, crystallographic and computational investigations of peptides, proteins and bisphosphonates : new paradigms for rational drug design / ». 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3337869.
Texte intégralRésumé :
Thesis (Ph. D.)--University of Illinois at Urbana-Champaign, 2008.Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6637. Adviser: Eric Oldfield. Includes bibliographical references. Available on microfilm from Pro Quest Information and Learning.
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Lima, Adriana Filipa Soares. « Genetic modification of a bacteriophage to create a multifunctional drug delivery particle ». Master's thesis, 2016. http://hdl.handle.net/1822/47560.
Texte intégralRésumé :
Dissertação de mestrado em BioengenhariaBreast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females worldwide, with an estimated 1.7 million new cases and 521,900 deaths in 2012. Conventional treatments, such as chemotherapy and radiotherapy, continue to be the base of cancer therapy. These types of treatments non-specifically target any dividing cells, which in the case of chemotherapy, results in an indiscriminate drug distribution and severe toxicity for patients associated to a poor distribution and penetration of the drugs. To solve this problem and improve patient’s lifestyle, it is of utmost importance the development of new targeted therapies that eventually eliminate only cancer cells. This work aimed to develop a phage-based nanoparticle that will be used as a carrier for cytotoxic drugs in order to decrease drugs concentration in situ. To achieve this goal, the M13 filamentous bacteriophage was genetically modified to display, on its surface, HIV-Tat cell-penetrating peptides, which allows the internalization of the phage particles towards breast cancer cells. Genetically modified phages were then conjugated with the doxorubicin anti-carcinogenic drug, which was expected to result in a lower, controlled and in situ cytotoxic payload. Despite M13 phage has been genetically modified with success and proved to penetrate the cells, it appears to have no enhanced cytotoxic activity when compared to the free drug effect. In the future the phages obtainded in this work should be genetically modified with a sequencence encoding for a recognition peptide to discriminate between cancerous and healthy cells, thereby creating a targeted cytotoxic particle.
O cancro da mama é o cancro mais frequentemente diagnosticado e a principal causa de morte por cancro entre as mulheres em todo o mundo, tendo sido estimados cerca de 1,7 milhões de novos casos e 521,900 mortes em 2012. Os tratamentos convencionais, como a quimioterapia e a radioterapia, continuam a ser a base terapêutica deste tipo de doença. Contudo, estes tipos de tratamentos não são específicos tendo como alvo todas as células em divisão, sendo que, no caso da quimioterapia, há uma distribuição e penetração indiscriminada de drogas altamente citotóxicas, resultando na deteriorazação física dos pacientes. Para resolver este problema e melhorar o estilo de vida do paciente, têm vindo a desenvolver-se novas terapias direcionadas, com o objectivo de eliminar apenas as células cancerosas. Este trabalho tem como objectivo desenvolver uma nanopartícula, à base de bacteriofagos, de forma a transportar drogas citotóxicas e diminuir a sua concentração in situ. Para atingir este objetivo, o bacteriofago filamentoso M13 foi geneticamente modificado, com o propósito deste exibir o péptido de internalização celular HIV-Tat à sua superfície, através da técnica de phage display. De seguida os fagos genéticamente modificados foram químicamente conjugados com um fármaco anticancerígeno, a doxorrubicina, sendo assim esperado um payload citotóxico mais baixo e controlado, no local do tumor. Apesar do fago ter sido genéticamente modificado com sucesso e ter mostrado internalizar nas células tumorais de cancro de mama, este parece não ter qualquer actividade citotóxica quando comparado com o efeito da droga livre. No futuro o fago construido neste trabalho deverá ser geneticamente modificado com a sequencia de um peptido de reconhecimento de forma a discriminar entre celulas cancerígenas e saudáveis, criando assim uma particula citotóxica direcionada.
Livres sur le sujet "Generic peptide drug"
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NATO Advanced Research Workshop on Advanced Drug Delivery Systems for Peptides and Proteins (1986 Copenhagen, Denmark). Delivery systems for peptide drugs. New York : Plenum Press, 1986.
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2
Proteins, enzymes, genes : The interplay of chemistry and biology. New Haven, CT : Yale University Press, 1999.
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Jun-Lin, Guan, dir. Signaling through cell adhesion molecules. Boca Raton, Fla : CRC Press, 1999.
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Davis, S. S. Delivery Systems for Peptide Drugs. Springer, 2013.
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Tomlinson, E., Lisbeth Illum et S. S. Davis. Delivery Systems for Peptide Drugs. Springer London, Limited, 2013.
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Delivery Systems for Peptide Drugs (Nato Asi Series a, Life Sciences, Vol 125) (Nato Science Series : A:). Springer, 1987.
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Dhagat, Swasti, Jujjvarapu Satya Eswari et Manisha Yadav. Computer-Aided Design of Antimicrobial Lipopeptides As Prospective Drug Candidates. Taylor & Francis Group, 2019.
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Dhagat, Swasti, Jujjvarapu Satya Eswari et Manisha Yadav. Computer-Aided Design of Antimicrobial Lipopeptides As Prospective Drug Candidates. Taylor & Francis Group, 2019.
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Dhagat, Swasti, Jujjvarapu Satya Eswari et Manisha Yadav. Computer-Aided Design of Antimicrobial Lipopeptides As Prospective Drug Candidates. Taylor & Francis Group, 2019.
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Jujjavarapu, Satya Eswari, Swasti Dhagat et Manisha Yadav. Computer-Aided Design of Antimicrobial Lipopeptides As Prospective Drug Candidates. Taylor & Francis Group, 2021.
Trouver le texte intégralChapitres de livres sur le sujet "Generic peptide drug"
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Furlong, Michael T. « Generic Peptide Strategies for LC-MS/MS Bioanalysis of Human Monoclonal Antibody Drugs and Drug Candidates ». Dans Protein Analysis using Mass Spectrometry, 161–81. Hoboken, NJ, USA : John Wiley & Sons, Inc., 2017. http://dx.doi.org/10.1002/9781119371779.ch13.
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Belda, Ignasi, Xavier Llorà, Marc Martinell, Teresa Tarragó et Ernest Giralt. « Computer-Aided Peptide Evolution for Virtual Drug Design ». Dans Genetic and Evolutionary Computation – GECCO 2004, 321–32. Berlin, Heidelberg : Springer Berlin Heidelberg, 2004. http://dx.doi.org/10.1007/978-3-540-24854-5_34.
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Scocchi, Marco, Maura Mattiuzzo, Monica Benincasa, Nikolinka Antcheva, Alessandro Tossi et Renato Gennaro. « Investigating the Mode of Action of Proline-Rich Antimicrobial Peptides Using a Genetic Approach : A Tool to Identify New Bacterial Targets Amenable to the Design of Novel Antibiotics ». Dans Peptide-Based Drug Design, 161–76. Totowa, NJ : Humana Press, 2008. http://dx.doi.org/10.1007/978-1-59745-419-3_9.
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Kubiak, T. M., R. A. Martin, R. M. Hillman, J. F. Caputo, G. R. Alaniz, W. H. Claflin, D. L. Cleary et W. M. Moseley. « N-terminally extended analogs of bgrf with a general formula [X -1,Y 0, Leu 27]bGRF(1–29)NH2 as pro-drugs and potential targets for processing by plasma dipeptidylpeptidase IV (DPP-IV) ». Dans Peptides, 859–61. Dordrecht : Springer Netherlands, 1994. http://dx.doi.org/10.1007/978-94-011-0683-2_288.
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Sharma, Mani, Jyoti Joshi, Neeraj Kumar Chouhan, Mamta N. Talati, Sandeep Vaidya et Abhiram Kumar. « Liposome-A Comprehensive Approach for Researchers ». Dans Molecular Pharmacology. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.93256.
Texte intégralRésumé :
Bangham was first to develop these spherical-shaped nano-vesicles called liposomes in the early 1960s. Today, liposomes have emerged as crucial tools for bettering the delivery of drugs that majorly includes-antifungal drug, peptide hormones, enzymes, vaccines antimicrobial agents, drugs against cancer, and genetic materials. Following the different manufacturing practices and versatile properties liposomes can be categorized in various parameters of size, charge, poly-dispersity index, encapsulation efficiency, solubility properties, and lamellarity. Alteration in such parameters elevates the loading and bioavailability of a drug by giving more clear target specification, desired or controlled release. This bibliographic chapter provides a comprehensive overview of methods for the preparation of liposomes with other perspectives that majorly includes—physio-chemical characteristics, dosage regimen, advantages over other delivery systems, approved liposomal based drugs and other ongoing drugs in clinical trials. It will help researchers to breakthrough more structurally successful delivery vehicles depending upon their various physic-chemical properties.
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Li, Jie Jack. « Reflections ». Dans Laughing Gas, Viagra, and Lipitor. Oxford University Press, 2006. http://dx.doi.org/10.1093/oso/9780195300994.003.0014.
Texte intégralRésumé :
In this book, I have chronicled eight categories of medicines. As a testament to the changing times, the old European master-apprentice relationship between drug discoverers is a thing of the past. This truth is exemplified by the feud between Selman Waksman and Albert Schatz (see chapter 2). I have no doubt that Waksman sincerely believed that he was the one responsible for the discovery of streptomycin. After all, streptomycin was the fruit of decades of his endeavor with soil microbiology in general and actinomycetes in particular. Schatz happened to be at the right place at the right time. Waksman’s conviction would have been completely acceptable if it had taken place just a century ago. Since the new millennium, vilifying the pharmaceutical industry has become fashionable. One of the crimes that the pharmaceutical industry is accused of committing involves the so-called me-too drugs. Even Merck’s former head of research Ed Scolnick once declared: “We at Merck do not do me-toos, if it is not innovative, we are not interested.” But history is replete with examples in which incremental improvements of a prototype yielded much better drugs. The first ACE inhibitor was teprotide, a peptide with nine amino acids, inspired by a Brazilian snake venom extract. Peptides did not survive in the stomach juice, which broke them down into amino acids. Therefore, the prototype teprotide could be used only by IV injection. With brilliant insight, David Cushman and Miguel Ondetti at Squibb Pharmaceuticals designed and synthesized captopril. Captopril was the first oral ACE inhibitor, which contributed tremendously to the management of hypertension. In theory, captopril is indeed a “me-too” drug to teprotide, but most patients would certainly prefer to take an oral drug than to have injections for the same purpose. Because captopril has a short duration of action, it has to be taken more than once a day. It possessed a trio of shortcomings: bone marrow suppression (due to a decrease in circulating white blood cells), skin rash, and a loss of taste.
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Mohan, C. Gopi, et Shikhar Gupta. « QSAR Models towards Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease ». Dans Oncology, 591–636. IGI Global, 2017. http://dx.doi.org/10.4018/978-1-5225-0549-5.ch022.
Texte intégralRésumé :
Alzheimer's Disease (AD) is a multifactorial neurological syndrome with the combination of aging, genetic, and environmental factors triggering the pathological decline. Interestingly, the importance of the Acetylcholinesterase (AChE) enzyme has increased due to its involvement in the ß-amyloid peptide fibril formation during AD pathogenesis. In silico technique, QSAR has proven its usefulness in pharmaceutical research for the design/optimization of new chemical entities. Further, QSAR method advanced the scope of rational drug design and the search for the mechanism of drug action. It is a well-established fact that the chemical and pharmaceutical effects of a compound are closely related to its physico-chemical properties, which can be calculated by various methods from the compound structure. This chapter focuses on different Quantitative Structure-Activity Relationship (QSAR) studies carried out for a variety of cholinesterase inhibitors for the treatment of AD. These predictive models will be potentially used for further designing better and safer drugs against AD.
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Mohan, C. Gopi, et Shikhar Gupta. « QSAR Models towards Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease ». Dans Quantitative Structure-Activity Relationships in Drug Design, Predictive Toxicology, and Risk Assessment, 354–99. IGI Global, 2015. http://dx.doi.org/10.4018/978-1-4666-8136-1.ch010.
Texte intégralRésumé :
Alzheimer's Disease (AD) is a multifactorial neurological syndrome with the combination of aging, genetic, and environmental factors triggering the pathological decline. Interestingly, the importance of the Acetylcholinesterase (AChE) enzyme has increased due to its involvement in the ß-amyloid peptide fibril formation during AD pathogenesis. In silico technique, QSAR has proven its usefulness in pharmaceutical research for the design/optimization of new chemical entities. Further, QSAR method advanced the scope of rational drug design and the search for the mechanism of drug action. It is a well-established fact that the chemical and pharmaceutical effects of a compound are closely related to its physico-chemical properties, which can be calculated by various methods from the compound structure. This chapter focuses on different Quantitative Structure-Activity Relationship (QSAR) studies carried out for a variety of cholinesterase inhibitors for the treatment of AD. These predictive models will be potentially used for further designing better and safer drugs against AD.
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P. Okoh, Michael, et Lukman A. Alli. « Recent Progress in Drug Repurposing Using Protein Variants and Amino Acids in Disease Phenotypes/Disorders ». Dans Drug Repurposing - Molecular Aspects and Therapeutic Applications [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.102571.
Texte intégralRésumé :
Life is constituted of large group of macromolecule, functional and structural called “Protein,” made of amino acids (AA), and linked with peptide bonds with specific protein unique sequences. Variations in proteins are thought to have diverse effects with consequences on structure, stability, interactions, pH, enzymatic activity, abundance and other properties. Variants can be of genetic origin or it could occur de novo at the post-translational protein level. The sequence of amino acids defines protein structure and functions. Protein is involved in several critical functions like the physical cell-cell communication. Breakthrough in molecular science has shown that, to develop drugs for managing a disease-associated variations requires understanding of consequences of variants on the function of the affected protein and the impact on the pathways, in which protein is involved. Using biophysical/bioinformatics methods, immense amount of variation data generated is handled-connected to disease phenotypes. Obviously, there remain continuous needs for the combinations of genetic probing methods/bioinformatics, to predict single-nucleotide variations (SNV), for effective rational drug design that would embrace naturally occurring bioactive components of plant origin, towards the effective management of disease phenotype emanating from protein and amino acid variations. This, well thought out and synchronized concept, remains a way forward.
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Rachamalla, Harikrishnareddy, Anubhab Mukherjee et Manash K. Paul. « Nanotechnology Application and Intellectual Property Right Prospects of Mammalian Cell Culture ». Dans Cell Culture [Working Title]. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.99146.
Texte intégralRésumé :
The significant challenges faced by modern-day medicine include designing a target-specific drug delivery system with a controlled release mechanism, having the potential to avoid opsonization and reduce bio-toxicity. Nanoparticles are materials with nanoscale dimensions and maybe natural and synthetic in origin. Engineered nano-sized materials are playing an indispensable role in the field of nanomedicine and nanobiotechnology. Besides, engineered nano-sized particles impart therapeutic applications with enhanced specificity because of their unique bespoke properties. Moreover, such application-customized nanoparticles offer an enormous possibility for their compatibility with different biological molecules like proteins, genetic materials, cell membranes, and organelles at the nano-bio frame. Besides, surface functionalization with targeting moieties such as small molecule ligands, monoclonal antibodies, aptamers, cell-penetrating peptides, and proteins facilitate nanoparticle-based specific tissue targeting. This review summarizes some of the advances in nanoparticle-based therapeutics and theranostics. A better understanding of idealistic preparation methods, physicochemical attributes, surface functionalization, biocompatibility can empower the potential translation of nanomaterials from the ‘bench-to-bedside’. In modern-day medicine, engineered nanoparticles have a wide range of demands ranging from bio-imaging, theranostics, tissue engineering, sensors, drug and nucleic acid delivery, and other pharmaceuticals applications. 2D and 3D mammalian cell-based assays are widely used to model diseases, screening of drugs, drug discovery, and toxicity analyses. Recent advances in cell culture technology and associated progress in nanotechnology have enabled researchers to study a wide variety of physiologically relevant questions. This chapter explores the properties of nanoparticles, different targeted delivery methods, biological analysis, and theranostics. Moreover, this chapter also emphasizes biosafety and bioethics associated with mammalian cell culture and discusses the significance of intellectual property rights from an industrial and academic perspective.