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Noh, Gyubin, Taekwang Keum, Jo-Eun Seo, Santosh Bashyal, Nyeon-Sik Eum, Min Kweon, Sooyeun Lee, Dong Sohn y Sangkil Lee. "Iontophoretic Transdermal Delivery of Human Growth Hormone (hGH) and the Combination Effect of a New Type Microneedle, Tappy Tok Tok®". Pharmaceutics 10, n.º 3 (7 de septiembre de 2018): 153. http://dx.doi.org/10.3390/pharmaceutics10030153.
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Transdermal drug administration presents several advantages and it is therefore favorable as an alternative drug delivery route. However, transdermal delivery of biopharmaceutical drugs is made difficult by the skin barrier. Microneedle application and iontophoresis are strategies which can be used to overcome this barrier. Therefore, recombinant human growth hormone (rhGH) was used as a model macromolecular drug and was transdermally delivered using microneedle application and iontophoresis. Methylene blue staining, stereomicroscopy and scanning electron microscope (SEM) imaging were used to characterize the microchannels produced. To optimize the iontophoresis protocol, the effects of molecular charge and current density on transdermal delivery were evaluated in an in vitro permeation study using excised rat skin tissues. Using the optimized iontophoresis protocol, the combination effects of iontophoretic delivery via microchannels were evaluated in three different experimental designs. The flux obtained with anodal iontophoresis in citrate buffer was approximately 10-fold higher that that with cathodal iontophoresis in phosphate buffered saline (PBS). Flux also increased with current density in anodal iontophoresis. The combination of iontophoresis and microneedle application produced higher flux than single application. These results suggest that anodal iontophoresis with higher current density enhances the permeation of macromolecules through microchannels created by microneedles. In conclusion, the combination of iontophoresis and microneedles is a potential strategy for the enhancement of transdermal delivery of macromolecular drugs.
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Selaković, Života y Bogdan Šolaja. "ADVANCES IN TACKLING FILOVIRUSES". Contributions, Section of Natural, Mathematical and Biotechnical Sciences 39, n.º 2 (28 de diciembre de 2018): 83. http://dx.doi.org/10.20903/csnmbs.masa.2018.39.2.127.
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Filoviruses are virulent pathogens that cause deadly haemorrhagic fever in humans and non-human primates. There is currently no approved drug or vaccine to tackle this disease. Two vaccine platforms that use adenovirus vectors have completed phase I studies, while a recombinant vesicular stomatitis virus-based vaccine has successfully complet-ed a phase III trial. Intricate macromolecular therapeutics have also been developed, most notably those based on anti-bodies or interfering RNA or RNA-surrogates. Most small molecules active against filoviruses have not yet advanced to clinical trials, except favipiravir, which was proven to be safe, and GS-5734, which has entered trials.
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Callahan, Shellie M., Piyanuch Wonganan y Maria A. Croyle. "Molecular and macromolecular alterations of recombinant adenoviral vectors do not resolve changes in hepatic drug metabolism during infection". Virology Journal 5, n.º 1 (2008): 111. http://dx.doi.org/10.1186/1743-422x-5-111.
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Ferentz, Ann E. y Gerhard Wagner. "NMR spectroscopy: a multifaceted approach to macromolecular structure". Quarterly Reviews of Biophysics 33, n.º 1 (febrero de 2000): 29–65. http://dx.doi.org/10.1017/s0033583500003589.
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1. Introduction 292. Landmarks in NMR of macromolecules 322.1 Protein structures and methods development 322.1.1 Sequential assignment method 322.1.2 Triple-resonance experiments 342.1.3 Structures of large proteins 362.2 Protein–nucleic acid complexes 372.3 RNA structures 382.4 Membrane-bound systems 393. NMR spectroscopy today 403.1 State-of-the-art structure determination 413.2 New methods 443.2.1 Residual dipolar couplings 443.2.2 Direct detection of hydrogen bonds 443.2.3 Spin labeling 453.2.4 Segmental labeling 463.3 Protein complexes 473.4 Mobility studies 503.5 Determination of time-dependent structures 523.6 Drug discovery 534. The future of NMR 544.1 The ease of structure determination 544.2 The ease of making recombinant protein 554.3 Post-translationally modified proteins 554.4 Approaches to large and/or membrane-bound proteins 564.5 NMR in structural genomics 564.6 Synergy of NMR and crystallography in protein structure determination 565. Conclusion 576. Acknowledgements 577. References 57Since the publication of the first complete solution structure of a protein in 1985 (Williamson et al. 1985), tremendous technological advances have brought nuclear magnetic resonance spectroscopy to the forefront of structural biology. Innovations in magnet design, electronics, pulse sequences, data analysis, and computational methods have combined to make NMR an extremely powerful technique for studying biological macromolecules at atomic resolution (Clore & Gronenborn, 1998). Most recently, new labeling and pulse techniques have been developed that push the fundamental line-width limit for resolution in NMR spectroscopy, making it possible to obtain high-field spectra with better resolution than ever before (Dötsch & Wagner, 1998). These methods are facilitating the study of systems of ever-increasing complexity and molecular weight.
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Wu, Yu, Miora Rakotoarisoa, Borislav Angelov, Yuru Deng y Angelina Angelova. "Self-Assembled Nanoscale Materials for Neuronal Regeneration: A Focus on BDNF Protein and Nucleic Acid Biotherapeutic Delivery". Nanomaterials 12, n.º 13 (30 de junio de 2022): 2267. http://dx.doi.org/10.3390/nano12132267.
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Enabling challenging applications of nanomedicine and precision medicine in the treatment of neurodegenerative disorders requires deeper investigations of nanocarrier-mediated biomolecular delivery for neuronal targeting and recovery. The successful use of macromolecular biotherapeutics (recombinant growth factors, antibodies, enzymes, synthetic peptides, cell-penetrating peptide–drug conjugates, and RNAi sequences) in clinical developments for neuronal regeneration should benefit from the recent strategies for enhancement of their bioavailability. We highlight the advances in the development of nanoscale materials for drug delivery in neurodegenerative disorders. The emphasis is placed on nanoformulations for the delivery of brain-derived neurotrophic factor (BDNF) using different types of lipidic nanocarriers (liposomes, liquid crystalline or solid lipid nanoparticles) and polymer-based scaffolds, nanofibers and hydrogels. Self-assembled soft-matter nanoscale materials show favorable neuroprotective characteristics, safety, and efficacy profiles in drug delivery to the central and peripheral nervous systems. The advances summarized here indicate that neuroprotective biomolecule-loaded nanoparticles and injectable hydrogels can improve neuronal survival and reduce tissue injury. Certain recently reported neuronal dysfunctions in long-COVID-19 survivors represent early manifestations of neurodegenerative pathologies. Therefore, BDNF delivery systems may also help in prospective studies on recovery from long-term COVID-19 neurological complications and be considered as promising systems for personalized treatment of neuronal dysfunctions and prevention or retarding of neurodegenerative disorders.
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Coentro, João Q., Alessia di Nubila, Ulrike May, Stuart Prince, John Zwaagstra, Tero A. H. Järvinen y Dimitrios I. Zeugolis. "Dual drug delivery collagen vehicles for modulation of skin fibrosis in vitro". Biomedical Materials 17, n.º 2 (1 de marzo de 2022): 025017. http://dx.doi.org/10.1088/1748-605x/ac5673.
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Abstract Single molecule drug delivery systems have failed to yield functional therapeutic outcomes, triggering investigations into multi-molecular drug delivery vehicles. In the context of skin fibrosis, although multi-drug systems have been assessed, no system has assessed molecular combinations that directly and specifically reduce cell proliferation, collagen synthesis and transforming growth factor β1 (TGFβ1) expression. Herein, a core–shell collagen type I hydrogel system was developed for the dual delivery of a TGFβ trap, a soluble recombinant protein that inhibits TGFβ signalling, and Trichostatin A (TSA), a small molecule inhibitor of histone deacetylases. The antifibrotic potential of the dual delivery system was assessed in an in vitro skin fibrosis model induced by macromolecular crowding (MMC) and TGFβ1. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and high performance liquid chromatography analyses revealed that ∼50% of the TGFβ trap and ∼30% of the TSA were released from the core and shell compartments, respectively, of the hydrogel system after 10 d (longest time point assessed) in culture. As a direct consequence of this slow release, the core (TGFβ trap)/shell (TSA) hydrogel system induced significantly (p < 0.05) lower than the control group (MMC and TGFβ1) collagen type I deposition (assessed via SDS-PAGE and immunocytochemistry), α smooth muscle actin (αSMA) expression (assessed via immunocytochemistry) and cellular proliferation (assessed via DNA quantification) and viability (assessed via calcein AM and ethidium homodimer-I staining) after 10 d in culture. On the other hand, direct TSA-TGFβ supplementation induced the lowest (p < 0.05) collagen type I deposition, αSMA expression and cellular proliferation and viability after 10 d in culture. Our results illustrate the potential of core–shell collagen hydrogel systems for sustained delivery of antifibrotic molecules.
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Turbyfill, K. Ross, Kristen A. Clarkson, Edwin V. Oaks y Robert W. Kaminski. "From Concept to Clinical Product: A Brief History of the Novel Shigella Invaplex Vaccine’s Refinement and Evolution". Vaccines 10, n.º 4 (1 de abril de 2022): 548. http://dx.doi.org/10.3390/vaccines10040548.
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The Shigella invasin complex or Invaplex vaccine is a unique subunit approach to generate a protective immune response. Invaplex is a large, macromolecular complex consisting of the major Shigella antigens: lipopolysaccharide (LPS) and the invasion plasmid antigen (Ipa) proteins B and C. Over the past several decades, the vaccine has progressed from initial observations through pre-clinical studies to cGMP manufacture and clinical evaluations. The Invaplex product maintains unique biological properties associated with the invasiveness of virulent shigellae and also presents both serotype-specific epitopes, as well as highly conserved invasin protein epitopes, to the immunized host. The vaccine product has evolved from a native product isolated from wild-type shigellae (native Invaplex) to a more defined vaccine produced from purified LPS and recombinant IpaB and IpaC (artificial Invaplex). Each successive “generation” of the vaccine is derived from earlier versions, resulting in improved immunogenicity, homogeneity and effectiveness. The current vaccine, detoxified artificial Invaplex (InvaplexAR-Detox), was developed for parenteral administration by incorporating LPS with under-acylated lipid A. InvaplexAR-Detox has demonstrated an excellent safety and immunogenicity profile in initial clinical studies and is advancing toward evaluations in the target populations of children and travelers to endemic countries.
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Sochacka-Ćwikła, Aleksandra, Marcin Mączyński y Andrzej Regiec. "FDA-Approved Drugs for Hematological Malignancies—The Last Decade Review". Cancers 14, n.º 1 (24 de diciembre de 2021): 87. http://dx.doi.org/10.3390/cancers14010087.
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Hematological malignancies, also referred to as blood cancers, are a group of diseases involving abnormal cell growth and persisting in the blood, lymph nodes, or bone marrow. The development of new targeted therapies including small molecule inhibitors, monoclonal antibodies, bispecific T cell engagers, antibody-drug conjugates, recombinant immunotoxins, and, finally, Chimeric Antigen Receptor T (CAR-T) cells has improved the clinical outcomes for blood cancers. In this review, we summarized 52 drugs that were divided into small molecule and macromolecule agents, approved by the Food and Drug Administration (FDA) in the period between 2011 and 2021 for the treatment of hematological malignancies. Forty of them have also been approved by the European Medicines Agency (EMA). We analyzed the FDA-approved drugs by investigating both their structures and mechanisms of action. It should be emphasized that the number of targeted drugs was significantly higher (46 drugs) than chemotherapy agents (6 drugs). We highlight recent advances in the design of drugs that are used to treat hematological malignancies, which make them more effective and less toxic.
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Sellers, Drew L., Jamie M. Bergen, Russell N. Johnson, Heidi Back, John M. Ravits, Philip J. Horner y Suzie H. Pun. "Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration". Proceedings of the National Academy of Sciences 113, n.º 9 (17 de febrero de 2016): 2514–19. http://dx.doi.org/10.1073/pnas.1515526113.
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A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics.
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Ghosh, Samit, Prosenjit Sen, Mirella Ezban, Usha R. Pendurthi y L. Vijaya Mohan Rao. "Activity and Regulation of Long-Acting Factor VIIa Analogs." Blood 110, n.º 11 (16 de noviembre de 2007): 3141. http://dx.doi.org/10.1182/blood.v110.11.3141.3141.
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Abstract Recombinant coagulation factor VIIa (rFVIIa) has proven to be a safe and effective drug for treatment of bleeding episodes in hemophilia patients with inhibitors. However, rFVIIa is cleared from the circulation relatively fast, with circulating half-life of about 2–4 h, requiring repeated administration of rFVIIa for the effective treatment. Therefore, development of FVIIa analogs that could remain in the circulation for a longer period of time would be of a great value for improving the treatment options of rFVIIa. e.g., by prophylaxis. PEGylation of plasma proteins was shown to extend their circulatory half-lives but the PEGylation may also disrupt macromolecular interactions. In the present study we characterized the interaction of two glycoPEGylated analogs of rFVIIa, rFVIIa-10K PEG and rFVIIa-40K PEG, with its cofactor tissue factor (TF), substrate factor X (FX) and plasma inhibitors, tissue factor pathway inhibitor (TFPI) and antithrombin (AT). Both the PEGylated FVIIa analogs exhibited similar amidolytic activity as of wild-type rFVIIa (wt-rFVIIa) in the absence or presence of relipidated TF. The analogs were as effective as wt-rFVIIa in activating FX in the absence of TF. No significant differences were found between the PEGylated rFVIIa analogs and wt-rFVIIa in TF-dependent FX activation at saturating concentrations of rFVIIa, however, at lower concentrations of rFVIIa (10 to 50 pM), rFVIIa-10K PEG and rFVIIa-40K PEG activated FX at a slightly lower rate, 50% and 75%, respectively, of wt-rFVIIa. Further studies revealed that both AT/heparin and TFPI inhibited the PEGylated rFVIIa-TF complexes effectively but slightly at a lower rate compared to that was noted for wt-rFVIIa-TF. TFPI-Xa inhibited the PEGylated rFVIIa-TF and wt-rFVIIa-TF at a similar rate. On unperturbed HUVEC, wt-FVIIa (10 nM) could activate FX, albeit slowly, (1.7 nM/h) and the PEGylated rFVIIa activated FX even at much lower rates (0.23 nM/h for rFVIIa-10K PEG and 0.15 nM/h for rFVIIa-40K PEG). On stimulated HUVEC expressing TF, the PEGylated rFVIIa variants were slightly less effective at lower concentrations compared to wt-rFVIIa in activating FX, but no significant differences were found among them in activating factor X at saturating concentrations of rFVIIa (80–100 nM/h). The PEGylated rFVIIa analogs bound to cell surface TF were inhibited by TFPI-Xa complex at a similar rate as that was observed for wt-rFVIIa (IC50 in nM: 0.102 ± 0.032 for wt-rFVIIa, 0.111 ± 0.024 for rFVIIa-10K PEG, and 0.096 ± 0.019 for rFVIIa-40K PEG). AT/heparin inhibited rFVIIa-10K PEG bound to endothelial cell TF at a similar rate as it inhibited wt-rFVIIa (IC50 in μg/ml: wt-rFVIIa, 3.42 ± 068; rFVIIa-10K PEG, 3.56 ± 0.073), but the inhibition rate was slightly lower for rFVIIa-40K PEG bound to TF (IC50 5.92 ± 0.44 μg/ml). Overall, our present data suggest that long-acting PEGylated FVIIa analogs retain full enzymatic activity and can interact TF and FX effectively, and are inhibited by AT/heparin and TFPI-Xa as for wt-rFVIIa. Although the pegylated rFVIIa variants exhibited somewhat lower affinity towards TF, this may not critically affect the TF-driven FXa generation. Further work is needed to fully characterize these molecules.
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Baldwin, Enoch P., Shelley S. Martin, Jonas Abel, Kathy A. Gelato, Hanseong Kim, Peter G. Schultz y Stephen W. Santoro. "A Specificity Switch in Selected Cre Recombinase Variants Is Mediated by Macromolecular Plasticity and Water". Chemistry & Biology 10, n.º 11 (noviembre de 2003): 1085–94. http://dx.doi.org/10.1016/j.chembiol.2003.10.015.
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Klener Jr, Pavel, Tomas Etrych y Pavel Klener. "Biological Therapy of Hematologic Malignancies: Toward a Chemotherapy- free Era". Current Medicinal Chemistry 26, n.º 6 (13 de mayo de 2019): 1002–18. http://dx.doi.org/10.2174/0929867324666171006144725.
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:Less than 70 years ago, the vast majority of hematologic malignancies were untreatable diseases with fatal prognoses. The development of modern chemotherapy agents, which had begun after the Second World War, was markedly accelerated by the discovery of the structure of DNA and its role in cancer biology and tumor cell division. The path travelled from the first temporary remissions observed in children with acute lymphoblastic leukemia treated with single-agent antimetabolites until the first cures achieved by multi-agent chemotherapy regimens was incredibly short. Despite great successes, however, conventional genotoxic cytostatics suffered from an inherently narrow therapeutic index and extensive toxicity, which in many instances limited their clinical utilization. In the last decade of the 20th century, increasing knowledge on the biology of certain malignancies resulted in the conception and development of first molecularly targeted agents designed to inhibit specific druggable molecules involved in the survival of cancer cells. Advances in technology and genetic engineering enabled the production of structurally complex anticancer macromolecules called biologicals, including therapeutic monoclonal antibodies, antibody-drug conjugates and antibody fragments. The development of drug delivery systems (DDSs), in which conventional drugs were attached to various types of carriers including nanoparticles, liposomes or biodegradable polymers, represented an alternative approach to the development of new anticancer agents. Despite the fact that the antitumor activity of drugs attached to DDSs was not fundamentally different, the improved pharmacokinetic profiles, decreased toxic side effects and significantly increased therapeutic indexes resulted in their enhanced antitumor efficacy compared to conventional (unbound) drugs.:Approval of the first immune checkpoint inhibitor for the treatment of cancer in 2011 initiated the era of cancer immunotherapy. Checkpoint inhibitors, bispecific T-cell engagers, adoptive T-cell approaches and cancer vaccines have joined the platform so far, represented mainly by recombinant cytokines, therapeutic monoclonal antibodies and immunomodulatory agents. In specific clinical indications, conventional drugs have already been supplanted by multi-agent, chemotherapy-free regimens comprising diverse immunotherapy and/or targeted agents. The very distinct mechanisms of the anticancer activity of new immunotherapy approaches not only call for novel response criteria, but might also change fundamental treatment paradigms of certain types of hematologic malignancies in the near future.
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Xu, Maokai, Maria Antonova, Pavel Salavei, Katharina Illek, Ana Valeria Meléndez, Ramin Omidvar, Roland Thuenauer, Olga Makshakova y Winfried Römer. "Dimeric Lectin Chimeras as Novel Candidates for Gb3-Mediated Transcytotic Drug Delivery Through Cellular Barriers". Pharmaceutics 15, n.º 1 (9 de enero de 2023): 225. http://dx.doi.org/10.3390/pharmaceutics15010225.
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Receptor-mediated transcytosis is an elegant and promising strategy for drug delivery across biological barriers. Here, we describe a novel ligand–receptor pair based on a dimeric, engineered derivative of the Pseudomonas aeruginosa lectin LecA, here termed Di-LecA, and the host cell glycosphingolipid Gb3. We characterized the trafficking kinetics and transcytosis efficiencies in polarized Gb3-positive and -negative MDCK cells using mainly immunofluorescence in combination with confocal microscopy. To evaluate the delivery capacity of dimeric LecA chimeras, EGFP was chosen as a fluorescent model protein representing macromolecules, such as antibody fragments, and fused to either the N- or C-terminus of monomeric LecA using recombinant DNA technology. Both LecA/EGFP fusion proteins crossed cellular monolayers in vitro. Of note, the conjugate with EGFP at the N-terminus of LecA (EGFP-LecA) showed a higher release rate than the conjugate with EGFP at the C-terminus (LecA-EGFP). Based on molecular dynamics simulations and cross-linking studies of giant unilamellar vesicles, we speculate that EGFP-LecA tends to be a dimer while LecA-EGFP forms a tetramer. Overall, we confidently propose the dimeric LecA chimeras as transcytotic drug delivery tools through Gb3-positive cellular barriers for future in vivo tests.
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Desjardins, Annick, John Howard Sampson, Katherine B. Peters, Tulika Ranjan, Gordana Vlahovic, Stevie Threatt, James Emmett Herndon et al. "Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma." Journal of Clinical Oncology 31, n.º 15_suppl (20 de mayo de 2013): 2094. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2094.
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2094 Background: Current therapies for glioblastoma are limited by ineffective delivery beyond the blood-brain barrier, limited diffusion of macromolecules, and lack of tumor specificity. Sustained direct intracerebral infusion at slow flow rates [convection-enhanced delivery (CED)] can overcome delivery barriers. PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. We report the results of an ongoing phase I study evaluating PVSRIPO when delivered by CED. Methods: Eligible on study are adult patients with: 1-5 cm of measurable supratentorial recurrent glioblastoma ≥1cm away from the ventricles; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; KPS ≥70%; and positive anti-poliovirus titer. PVSRIPO is delivered intratumorally by CED over 6.5 hours. PVSRIPO dose escalation is accomplished by increasing agent concentration, allowing flow-rate and infusion volume to remain constant. Two-step continual reassessment method is used for dose escalation, with one patient each treated on dose levels 1-4, and a possibility of up to 13 patients on dose level 5. Results: Thus far, a total of five patients have been treated on study. No related or unrelated grade 3 or higher adverse events have been observed. Grade 1 adverse events possibly related to the study drug or procedure include one each of fever, cough, nasal congestion, vomiting, headache, hemiparesis, and lethargy. Grade 2 adverse events include one each of diarrhea and seizure. Patient #1 had failed bevacizumab prior to enrollment and remains disease free more than 9 months post PVSRIPO. Two more patients are disease free 8+ and 2+ months post treatment, respectively. One patient had pathology confirmed disease recurrence two months post treatment and one patient came off study due to clinical decline four months post treatment. Conclusions: Infusion of PVSRIPO via CED is safe thus far and encouraging efficacy results are observed. Updated results will be presented. Clinical trial information: NCT 01491893.
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Barbour, Tara, Krystyna Cwiklinski, Richard Lalor, John Pius Dalton y Carolina De Marco Verissimo. "The Zoonotic Helminth Parasite Fasciola hepatica: Virulence-Associated Cathepsin B and Cathepsin L Cysteine Peptidases Secreted by Infective Newly Excysted Juveniles (NEJ)". Animals 11, n.º 12 (8 de diciembre de 2021): 3495. http://dx.doi.org/10.3390/ani11123495.
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Fasciolosis caused by Fasciola hepatica is a major global disease of livestock and an important neglected helminthiasis of humans. Infection arises when encysted metacercariae are ingested by the mammalian host. Within the intestine, the parasite excysts as a newly excysted juvenile (NEJ) that penetrates the intestinal wall and migrates to the liver. NEJ excystment and tissue penetration are facilitated by the secretion of cysteine peptidases, namely, cathepsin B1 (FhCB1), cathepsin B2 (FhCB2), cathepsin B3 (FhCB3) and cathepsin L3 (FhCL3). While our knowledge of these peptidases is growing, we have yet to understand why multiple enzymes are required for parasite invasion. Here, we produced functional recombinant forms of these four peptidases and compared their physio-biochemical characteristics. Our studies show great variation of their pH optima for activity, substrate specificity and inhibitory profile. Carboxy-dipeptidase activity was exhibited exclusively by FhCB1. Our studies suggest that, combined, these peptidases create a powerful hydrolytic cocktail capable of digesting the various host tissues, cells and macromolecules. Although we found several inhibitors of these enzymes, they did not show potent inhibition of metacercarial excystment or NEJ viability in vitro. However, this does not exclude these peptidases as targets for future drug or vaccine development.
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Hastings, R. C., T. P. Gillis, J. L. Krahenbuhl y S. G. Franzblau. "Leprosy." Clinical Microbiology Reviews 1, n.º 3 (julio de 1988): 330–48. http://dx.doi.org/10.1128/cmr.1.3.330.
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Leprosy affects over 10 million people in the world. The disease is a model of graded cell-mediated immunity, in this case to the causative organism, Mycobacterium leprae. The clinical manifestations are due to (i) bacterial progression, (ii) immunologic responses of the host, (iii) peripheral nerve damage due to either or both bacterial progression and immunologic responses of the host, and (iv) preventable secondary deformities following nerve damage, which account for most of the stigma of the disease. Treatment modalities are now available to control or minimize the effects of bacterial progression, harmful immunologic responses of the host, peripheral nerve damage, and secondary deformities. Unique biochemical characteristics of M. leprae reside in the cell wall and associated macromolecules. Some of these molecules are potent immunogens in humans, while others constitute the structural integrity of the bacillus. Proteins of M. leprae are currently under intensive investigation as a result of deoxyribonucleic acid cloning of M. leprae genes. Structure-function and antigenic relationships of M. leprae proteins should become available by using recombinant deoxyribonucleic acid procedures coupled with T- and B-cell cloning to advance our understanding of the immunologic reactions encountered in Hansen's disease. Until recently, the study of the immunology of leprosy has been stymied by the lack of immunologically specific M. leprae antigens. The definition of specific antigens and production of recombinant and synthetic immunologic reagents have fostered state-of-the-art research efforts into new immunodiagnostic procedures and development of a leprosy vaccine. Also discussed is progress in understanding of the mechanism(s) underlying the M. leprae-specific immunodeficiency associated with lepromatous leprosy, including the role of suppressor T cells and defective macrophage function. Metabolic studies of M. leprae suggest intact catabolic pathways and energy generation with purine bases and catalase as possible growth factors. Special attention may also need to be given to biophysical parameters for eventual in vitro cultivation. Rapid in vitro systems, using quantitation of bacillary metabolic activity, may soon replace the lengthy mouse footpad test for determining the viability and drug susceptibility of the leprosy bacillus.
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Sønderby, Pernille, Günther Peters, Jens Bukrinski y Pernille Harris. "Combining SAXS with Rosetta for Identification of Native-like Protein Complexes". Acta Crystallographica Section A Foundations and Advances 70, a1 (5 de agosto de 2014): C424. http://dx.doi.org/10.1107/s2053273314095758.
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It is well-known that recombinant human serum albumin (rHSA) has the ability to stabilize proteins in solution preventing protein adsorption, aggregation and oxidation. For this reason, rHSA is used as an excipient in the formulation of protein pharmaceuticals. To shed light on the molecular interactions, we have studied a variety of protein drugs that are known to bind to rHSA and thereby being stabilized. We observe that the interactions depend on protein concentrations and differ significantly between protein drugs. One approach to study these systems on a molecular level is the combination of small angle X-ray scattering (SAXS) and in-silico modelling. SAXS can be used to identify the overall shape of proteins and protein complexes and ab initio models can be derived from the scattering profile using programs such as Dammif [1]. These programs allow us to assess the overall conformation of the macromolecular structures, but cannot provide detailed information on the molecular level regarding protein-protein interfaces of the complexes. Here, the Rosetta modelling suite, a multipurpose software suite, can be utilized to perform protein-protein docking and to study the complexes. The challenge in using the Rosetta docking tool [2] is the difficulties in efficiently identifying the native-like structure. For better identification we apply SAXS constrains during the docking procedure. Although the method has been applied previously [3], no benchmarking has been published regarding the relative success of using SAXS constrains. We therefore have conducted an elaborate benchmarking, where we have used SAXS constrains for determination of complexes of non-identical components using the Rosetta docking protocol. A pool of complex structures has been chosen to evaluate the difference between conventional docking and docking performed using SAXS constrains. This allows us to optimize the parameters in the protocol and pave the way to study unknown complex structures.
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Okeke, Ifeanyichukwu. "Molecular Docking and Analysis of some Ligands on Var2csTargetA". Journal of Health, Medicine, and Clinical Studies 1, n.º 1 (11 de diciembre de 2022): 26–46. http://dx.doi.org/10.58425/jhmcs.v1i1.84.
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Purpose: Prevalence of malaria during pregnancy and the spate of drug resistance by malaria parasites have constantly impacted maternal, perinatal and neonatal outcomes, especially in sub-Saharan Africa. This study aims to discover “in silico” non-recombinant molecules which can interact with placental chondroitin sulfate to inhibit binding or displace bound var2csA from the placenta in order to prevent pregnancy associated malaria.
Methodology: Protein data bank (rcsb.org) and PubChem were used to download the chemical structures of the receptor (3bqk) and those of the ligands. Canonical SMILES and other information about the ligands and the receptor were extracted from PubChem. Toxtree, Toxicity Estimation Software Tool (TEST), SwissADMET, Molinspiration and Lazar Toxicity Predicter were employed to test various toxicity and safety parameters of lead compounds. The structure of the macromolecule – chondroitin sulfate A (CSA) was retrieved by searching in the protein data bank (PDB) (rcsb.org/structure/3bqk); downloaded, and saved as a PDB format.
Findings: Molecular modeling and toxicity predictors used in this study indicated that among the ligands screened, IH3 had the lowest binding energy of -9.8Kcal/mol while var2csA had -2.8Kcal/mol. Var2csA is parasite’s adhesive protein. It was also observed that out of the 90 ligands (binding affinity range -9.8 to -1.0 Kcal/mol) screened, IH3 (-9.8Kcal/mol), FAD (-8.4 Kcal/mol), NDP (-8.2 Kcal/mol), A5A (-8.2 Kcal/mol), ABO (-8.1 Kcal/mol), IH2 (-7.8 Kcal/mol), 2RT (-7.7 Kcal/mol), CRO (-7.7 Kcal/mol) and IH1 (-7.7 Kcal/mol) appear to be the most promising lead compounds to occupy var2csA binding pocket in pCSA in order to prevent adhesion of malaria infected erythrocytes to the placenta. SwissADME and Molinspiration Cheminformatics for LogP (mean of 1.07 and range of -2.79 to 4.18) of the lead compounds showed no correlations between lipophilicity and interaction with receptors. Of all the compounds selected for analysis, only ABO and 2RT exhibited drug-like properties based on Ghose, Lipinski and Veber filters.
Conclusion: Data obtained from the study therefore suggests that IH3, FAD, NDP, A5A, ABO, IH2, 2RT, CRO, IH1 and var2csA make favourable lead candidates for targeting pCSA and therefore require further in vitro and in vivo evaluations.
Recommendation: This study therefore recommends the repurposing and extending the use of flavin adenine dinucleotide (FAD) to cover prophylactic management of malaria among pregnant women.
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"142. Molecular and Macromolecular Alterations of Recombinant Adenoviral Vectors Do Not Eliminate Changes in Hepatic Drug Metabolism". Molecular Therapy 11 (mayo de 2005): S57. http://dx.doi.org/10.1016/j.ymthe.2005.06.147.
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Johnson, Derrick, Erica Simmons, Sanofar Abdeen, Adam Kinne, Elijah Parmer, Sherri Rinker, Jennifer Thystrup, Swarna Ramaswamy y Ronald R. Bowsher. "Sensitive assay design for detection of anti-drug antibodies to biotherapeutics that lack an immunoglobulin Fc domain". Scientific Reports 11, n.º 1 (29 de julio de 2021). http://dx.doi.org/10.1038/s41598-021-95055-x.
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AbstractToday the evaluation of unwanted immunogenicity is a key component in the clinical safety evaluation of new biotherapeutic drugs and macromolecular delivery strategies. However, the evolving structural complexity in contemporary biotherapeutics creates a need for on-going innovation in assay designs for reliable detection of anti-drug antibodies, especially for biotherapeutics that may not be well-suited for testing by a bridging assay. We, therefore, initiated systematic optimization of the direct binding assay to adapt it for routine use in regulatory-compliant assays of serum anti-drug antibodies. Accordingly, we first prepared a SULFO-TAG labeled conjugate of recombinant Protein-A/G to create a sensitive electrochemiluminescent secondary detection reagent with broad reactivity to antibodies across many species. Secondly, we evaluated candidate blocker-diluents to identify ones producing the highest signal-to-noise response ratios. Lastly, we introduced use of the ratio of signal responses in biotherapeutic-coated and uncoated wells as a data transformation strategy to identify biological outliers. This alternative data normalization approach improved normality, reduced skewness, and facilitated application of a parametric screening cut point. We believe the optimized direct binding assay design employing SULFO-TAG labeled Protein-A/G represents a useful analytical design for detecting serum ADA to biotherapeutics that lack an immunoglobulin Fc domain.
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Altincekic, Nadide, Sophie Marianne Korn, Nusrat Shahin Qureshi, Marie Dujardin, Martí Ninot-Pedrosa, Rupert Abele, Marie Jose Abi Saad et al. "Large-Scale Recombinant Production of the SARS-CoV-2 Proteome for High-Throughput and Structural Biology Applications". Frontiers in Molecular Biosciences 8 (10 de mayo de 2021). http://dx.doi.org/10.3389/fmolb.2021.653148.
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The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.
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Linh, Nguyen Hue, Pham Thi Minh Hue, Nguyen Thi Thanh Binh, Bui Thanh Tung, Nguyen Thi Hai Yen y Nguyen Thanh Hai. "Protein Drugs". VNU Journal of Science: Medical and Pharmaceutical Sciences 38, n.º 3 (23 de septiembre de 2022). http://dx.doi.org/10.25073/2588-1132/vnumps.4436.
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Abstract: To serve health care, up to now, sciences have successfully developed many drugs with different effects. In general, in terms of chemical structure and effect characteristics, medicine can be classified into groups including inorganic drugs, small-molecule organic drugs, protein drugs (macromolecules), and recently a new group of drugs has been formed, separate from the protein drug class, which is the RNA drugs. In terms of pharmacological effects, in general, the mechanisms of protein drugs and small-molecule organic drugs do not differ too much because they all act at a particular stage related to pathological manifestations.
Protein drugs in the process of development have gone through many different stages, with different origins, from extraction and isolation from living tissues at an early stage to biosynthesis by recombinant technology and other modern biotechnology methods. To date, most of the proteins used in medicine have been produced through recombinant pathways, possibly through different semisynthetic steps to give the molecules more superior drug properties. Therefore, the group of protein drugs has an additional new name, biopharmaceuticals, to indicate their synthetic origin by biological methods.
The research, development, and application of protein drugs into clinical practice are of great significance, helping to enhance the ability of medicine to control and treat many difficult-to-treat diseases today, bringing many opportunities to have good health for people.
Keywords: Protein drugs, RNA drugs, Biopharmaceuticals, Inorganic drugs, Small-molecule organic drugs, Drug development, Cytokine, Enzyme, Hormone peptide, Stem cell, Recombinant technology, Biosimilar. *
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Zhang, Ying, Pan Guo, Zhe Ma, Peng Lu, Dereje Kebebe y Zhidong Liu. "Combination of cell-penetrating peptides with nanomaterials for the potential therapeutics of central nervous system disorders: a review". Journal of Nanobiotechnology 19, n.º 1 (23 de agosto de 2021). http://dx.doi.org/10.1186/s12951-021-01002-3.
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AbstractAlthough nanomedicine have greatly developed and human life span has been extended, we have witnessed the soared incidence of central nervous system (CNS) diseases including neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease), ischemic stroke, and brain tumors, which have severely damaged the quality of life and greatly increased the economic and social burdens. Moreover, partial small molecule drugs and almost all large molecule drugs (such as recombinant protein, therapeutic antibody, and nucleic acid) cannot cross the blood–brain barrier. Therefore, it is especially important to develop a drug delivery system that can effectively deliver therapeutic drugs to the central nervous system for the treatment of central nervous system diseases. Cell penetrating peptides (CPPs) provide a potential strategy for the transport of macromolecules through the blood–brain barrier. This study analyzed and summarized the progress of CPPs in CNS diseases from three aspects: CPPs, the conjugates of CPPs and drug, and CPPs modified nanoparticles to provide scientific basis for the application of CPPs for CNS diseases.
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Shin, Hee Je, Sun Uk Bak, Ha Na La, Jin Sun Kang, Hwa Hyun Lee, Hyo Jung Eom, Byung Kyu Lee y Hyun Ah Kang. "Efficient transdermal delivery of functional protein cargoes by a hydrophobic peptide MTD 1067". Scientific Reports 12, n.º 1 (27 de junio de 2022). http://dx.doi.org/10.1038/s41598-022-14463-9.
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AbstractThe skin has a protective barrier against the external environment, making the transdermal delivery of active macromolecules very difficult. Cell-penetrating peptides (CPPs) have been accepted as useful delivery tools owing to their high transduction efficiency and low cytotoxicity. In this study, we evaluated the hydrophobic peptide, macromolecule transduction domain 1067 (MTD 1067) as a CPP for the transdermal delivery of protein cargoes of various sizes, including growth hormone-releasing hexapeptide-6 (GHRP-6), a truncated form of insulin-like growth factor-I (des(1-3)IGF-I), and platelet-derived growth factor BB (PDGF-BB). The MTD 1067-conjugated GHRP-6 (MTD-GHRP-6) was chemically synthesized, whereas the MTD 1067-conjugated des(1-3)IGF-I and PDGF-BB proteins (MTD-des(1-3)IGF-I and MTD-PDGF-BB) were generated as recombinant proteins. All the MTD 1067-conjugated cargoes exhibited biological activities identical or improved when compared to those of the original cargoes. The analysis of confocal microscopy images showed that MTD-GHRP-6, MTD-des(1-3)IGF-I, and MTD-PDGF-BB were detected at 4.4-, 18.8-, and 32.9-times higher levels in the dermis, respectively, compared to the control group without MTD. Furthermore, the MTD 1067-conjugated cargoes did not show cytotoxicity. Altogether, our data demonstrate the potential of MTD 1067 conjugation in developing functional macromolecules for cosmetics and drugs with enhanced transdermal permeability.
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Pervin, Sneha, Somsubhra Ghosh, Sankhadip Bose y Nandan Sarkar. "Human immune globulin 10% with recombinant human Hyaluronidase- A Review". Research Journal of Pharmacy and Technology, 6 de agosto de 2021, 4504–8. http://dx.doi.org/10.52711/0974-360x.2021.00783.
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Primary immunodeficiency disorder (PID) refers to a heterogeneous cluster of over 350 syndromes that upshot from defects in the immune system development or function. PIDs are broadly classified as disorders of adaptive immunity or innate immunity. The enhanced efficacy of human immune serum globulin 10% with recombinant human Hyaluronidase with comparison to blood vessel human gamma globulin is a very prospective open-label study for PID. Treatment of primary immunological disorder diseases (PIDD) with Subcutaneous(SC) infusions of immune gamma globulin headed by an injection of hyazyme to extend SC tissue porousness was evaluated in two consecutive, prospective, non-controlled, multi-center studies. HYQVIA could be a subcutaneously mediated medication to treat the primary immunological disorder in adults. ENHANZE® drug delivery technology relies on the proprietary rHuPH20 macromolecule that facilitates the SC delivery of co administered medical specialty. Recombinant Human Hyaluronidase works by degrading the glycosaminoglycan hyaluronan, which plays a role in resistance to excessive flow of fluid within the Subcutaneous matrix, limiting massive volume SC drug delivery, dispersion, and absorption. Co-administration of recombinant Hyazyme with partner therapies can overcome administration time and volume barriers associated with existing SC therapeutic formulations.
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Kwan, Tristan O. C., Stefan A. Kolek, Amy E. Danson, Rosana I. Reis, Ines S. Camacho, Patrick D. Shaw Stewart y Isabel Moraes. "Measuring Protein Aggregation and Stability Using High-Throughput Biophysical Approaches". Frontiers in Molecular Biosciences 9 (16 de mayo de 2022). http://dx.doi.org/10.3389/fmolb.2022.890862.
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Structure-function relationships of biological macromolecules, in particular proteins, provide crucial insights for fundamental biochemistry, medical research and early drug discovery. However, production of recombinant proteins, either for structure determination, functional studies, or to be used as biopharmaceutical products, is often hampered by their instability and propensity to aggregate in solution in vitro. Protein samples of poor quality are often associated with reduced reproducibility as well as high research and production expenses. Several biophysical methods are available for measuring protein aggregation and stability. Yet, discovering and developing means to improve protein behaviour and structure-function integrity remains a demanding task. Here, we discuss workflows that are made possible by adapting established biophysical methods to high-throughput screening approaches. Rapid identification and optimisation of conditions that promote protein stability and reduce aggregation will support researchers and industry to maximise sample quality, stability and reproducibility, thereby reducing research and development time and costs.
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Ji, Xuemei, Hongyan Wang, Yue Chen, Junfei Zhou y Yu Liu. "Recombinant expressing angiopep-2 fused anti-VEGF single chain Fab (scFab) could cross blood–brain barrier and target glioma". AMB Express 9, n.º 1 (15 de octubre de 2019). http://dx.doi.org/10.1186/s13568-019-0869-3.
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Abstract In 2009, the FDA approved bevacizumab for the treatment of adult patients diagnosed with recurrent glioblastoma. However, the poor permeability of the macromolecules across the blood–brain barrier, determined by multifactorial anatomical and physiological milieu, restricts the clinical therapeutic effect of bevacizumab. The low-density lipoprotein receptor related protein 1 (LRP1) is highly expressed in the endothelial cells of the brain capillary and the glioma cells. Angiopep-2 (ANG) is a 19-aa oligopeptide that can bind to LRP1 and penetrate the blood–brain barrier by receptor-mediated transport. Therefore, ANG can be used as a dual-targeting drug delivery carrier into the brain and the glioma sites. In this study, ANG gene was fused with the C-terminal domain of single-chain antigen binding fragment (scFab) of the anti-VEGF antibody and recombinant scFab-ANG protein was expressed and purified using Rosatte (DE3) strain. We confirmed that ANG could carry anti-VEGF-scFab, penetrate a three-dimensional model of the brain tumor, and cross the hCMEC/D3 monolayer in the in vitro blood–brain barrier model. The animal experiments demonstrated that 3 h after the tail intravenous protein injection, the fluorescent signals in the brains of the mice in the scFab-ANG group were stronger than that in the scFab group. Furthermore, the study of the in situ rat glioma model shows that scFab-ANG could target glioma while anti-VEGF-scFab could not. These findings indicate that scFab-ANG had stronger transepithelial permeability and glioma targeting capacity. Thus, it can be a potential candidate drug for glioblastoma therapy.
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Bittencourt, Daniela Matias de C., Paula Oliveira, Valquíria Alice Michalczechen-Lacerda, Grácia Maria Soares Rosinha, Justin A. Jones y Elibio L. Rech. "Bioengineering of spider silks for the production of biomedical materials". Frontiers in Bioengineering and Biotechnology 10 (9 de agosto de 2022). http://dx.doi.org/10.3389/fbioe.2022.958486.
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Spider silks are well known for their extraordinary mechanical properties. This characteristic is a result of the interplay of composition, structure and self-assembly of spider silk proteins (spidroins). Advances in synthetic biology have enabled the design and production of spidroins with the aim of biomimicking the structure-property-function relationships of spider silks. Although in nature only fibers are formed from spidroins, in vitro, scientists can explore non-natural morphologies including nanofibrils, particles, capsules, hydrogels, films or foams. The versatility of spidroins, along with their biocompatible and biodegradable nature, also placed them as leading-edge biological macromolecules for improved drug delivery and various biomedical applications. Accordingly, in this review, we highlight the relationship between the molecular structure of spider silk and its mechanical properties and aims to provide a critical summary of recent progress in research employing recombinantly produced bioengineered spidroins for the production of innovative bio-derived structural materials.
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Harrison, James, Georgina Lloyd, Maju Joe, Todd L. Lowary, Edward Reynolds, Hannah Walters-Morgan, Apoorva Bhatt, Andrew Lovering, Gurdyal S. Besra y Luke J. Alderwick. "Lcp1 Is a Phosphotransferase Responsible for Ligating Arabinogalactan to Peptidoglycan in Mycobacterium tuberculosis". mBio 7, n.º 4 (2 de agosto de 2016). http://dx.doi.org/10.1128/mbio.00972-16.
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ABSTRACT Mycobacterium tuberculosis , the etiological agent of tuberculosis (TB), has a unique cell envelope which accounts for its unusual low permeability and contributes to resistance against common antibiotics. The main structural elements of the cell wall consist of a cross-linked network of peptidoglycan (PG) in which some of the muramic acid residues are covalently attached to a complex polysaccharide, arabinogalactan (AG), via a unique α- l -rhamnopyranose–(1→3)-α- d -GlcNAc-(1→P) linker unit. While the molecular genetics associated with PG and AG biosynthetic pathways have been largely delineated, the mechanism by which these two major pathways converge has remained elusive. In Gram-positive organisms, the LytR-CpsA-Psr (LCP) family of proteins are responsible for ligating cell wall teichoic acids to peptidoglycan, through a linker unit that bears a striking resemblance to that found in mycobacterial arabinogalactan. In this study, we have identified Rv3267 as a mycobacterial LCP homolog gene that encodes a phosphotransferase which we have named Lcp1. We demonstrate that lcp1 is an essential gene required for cell viability and show that recombinant Lcp1 is capable of ligating AG to PG in a cell-free radiolabeling assay. IMPORTANCE Tuberculosis is an infectious disease caused by the bacterial organism Mycobacterium tuberculosis . Survival of M. tuberculosis rests critically on the integrity of its unique cell wall; therefore, a better understanding of how the genes and enzymes involved in cell wall assembly work is fundamental for us to develop new drugs to treat this disease. In this study, we have identified Lcp1 as an essential phosphotransferase that ligates together arabinogalactan and peptidoglycan, two crucial cell wall macromolecules found within the mycobacterial cell wall. The discovery of Lcp1 sheds new light on the final stages of mycobacterial cell wall assembly and represents a key biosynthetic step that could be exploited for new anti-TB drug discovery.
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Wang, Jiewen, Guangbo Kang, Haibin Yuan, Xiaocang Cao, He Huang y Ario de Marco. "Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment". Frontiers in Immunology 12 (18 de enero de 2022). http://dx.doi.org/10.3389/fimmu.2021.838082.
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Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative to conventional monoclonal antibodies also for clinical applications. Furthermore, they do not solely represent a substitute for monoclonal antibodies but their unique features allow expanding the applications of biotherapeutics and changes the pattern of disease treatment. Nanobodies possess the double advantage of being small and simple to engineer. This combination has promoted extremely diversified approaches to design nanobody-based constructs suitable for particular applications. Both the format geometry possibilities and the functionalization strategies have been widely explored to provide macromolecules with better efficacy with respect to single nanobodies or their combination. Nanobody multimers and nanobody-derived reagents were developed to image and contrast several cancer diseases and have shown their effectiveness in animal models. Their capacity to block more independent signaling pathways simultaneously is considered a critical advantage to avoid tumor resistance, whereas the mass of these multimeric compounds still remains significantly smaller than that of an IgG, enabling deeper penetration in solid tumors. When applied to CAR-T cell therapy, nanobodies can effectively improve the specificity by targeting multiple epitopes and consequently reduce the side effects. This represents a great potential in treating malignant lymphomas, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma and solid tumors. Apart from cancer treatment, multispecific drugs and imaging reagents built with nanobody blocks have demonstrated their value also for detecting and tackling neurodegenerative, autoimmune, metabolic, and infectious diseases and as antidotes for toxins. In particular, multi-paratopic nanobody-based constructs have been developed recently as drugs for passive immunization against SARS-CoV-2 with the goal of impairing variant survival due to resistance to antibodies targeting single epitopes. Given the enormous research activity in the field, it can be expected that more and more multimeric nanobody molecules will undergo late clinical trials in the next future.Systematic Review Registration