المؤلفون: Fink, Elissa A, Bardine, Conner, Gahbauer, Stefan, Singh, Isha, Detomasi, Tyler C, White, Kris, Gu, Shuo, Wan, Xiaobo, Chen, Jun, Ary, Beatrice, Glenn, Isabella, O'Connell, Joseph, O'Donnell, Henry, Fajtová, Pavla, Lyu, Jiankun, Vigneron, Seth, Young, Nicholas J, Kondratov, Ivan S, Alisoltani, Arghavan, Simons, Lacy M, Lorenzo‐Redondo, Ramon, Ozer, Egon A, Hultquist, Judd F, O'Donoghue, Anthony J, Moroz, Yurii S, Taunton, Jack, Renslo, Adam R, Irwin, John J, García‐Sastre, Adolfo, Shoichet, Brian K, Craik, Charles S

المصدر: Protein Science. 32(8)

مصطلحات موضوعية: Medicinal and Biomolecular Chemistry, Chemical Sciences, Lung, Prevention, Emerging Infectious Diseases, Infectious Diseases, Vaccine Related, Biodefense, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Humans, COVID-19, SARS-CoV-2, Pandemics, Protease Inhibitors, Molecular Docking Simulation, Viral Nonstructural Proteins, Antiviral Agents, major protease, SARS-COV-2, structure-based inhibitor, discoverydockinganti-viral, Biochemistry and Cell Biology, Computation Theory and Mathematics, Other Information and Computing Sciences, Biophysics, Biochemistry and cell biology, Medicinal and biomolecular chemistry

الوصف: Antiviral therapeutics to treat SARS-CoV-2 are needed to diminish the morbidity of the ongoing COVID-19 pandemic. A well-precedented drug target is the main viral protease (MPro ), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure-based approach, we docked 1.2 billion non-covalent lead-like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure-based techniques against MPro itself.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/61h336z6Test

المؤلفون: Kittirat Glab-ampai, Kanasap Kaewchim, Thanatsaran Saenlom, Watayagorn Thepsawat, Kodchakorn Mahasongkram, Nitat Sookrung, Wanpen Chaicumpa, Monrat Chulanetra

المصدر: International Journal of Molecular Sciences; Volume 23; Issue 12; Pages: 6587

مصطلحات موضوعية: SARS-CoV-2, major protease (3CL pro ), human single-chain antibody variable fragments (HuscFvs), cell-penetrating antibody, superantibody

جغرافية الموضوع: agris

الوصف: Broadly effective and safe anti-coronavirus agent is existentially needed. Major protease (3CLpro) is a highly conserved enzyme of betacoronaviruses. The enzyme plays pivotal role in the virus replication cycle. Thus, it is a good target of a broadly effective anti-Betacoronavirus agent. In this study, human single-chain antibodies (HuscFvs) of the SARS-CoV-2 3CLpro were generated using phage display technology. The 3CLpro-bound phages were used to infect Escherichia coli host for the production the 3CLpro-bound HuscFvs. Computerized simulation was used to guide the selection of the phage infected-E. coli clones that produced HuscFvs with the 3CLpro inhibitory potential. HuscFvs of three phage infected-E. coli clones were predicted to form contact interface with residues for 3CLpro catalytic activity, substrate binding, and homodimerization. These HuscFvs were linked to a cell-penetrating peptide to make them cell-penetrable, i.e., became superantibodies. The superantibodies blocked the 3CLpro activity in vitro, were not toxic to human cells, traversed across membrane of 3CLpro-expressing cells to co-localize with the intracellular 3CLpro and most of all, they inhibited replication of authentic SARS-CoV-2 Wuhan wild type and α, β, δ, and Omicron variants that were tested. The superantibodies should be investigated further towards clinical application as a safe and broadly effective anti-Betacoronavirus agent.

وصف الملف: application/pdf

العلاقة: Molecular Immunology; https://dx.doi.org/10.3390/ijms23126587Test

الإتاحة: https://doi.org/10.3390/ijms23126587Test

المؤلفون: Alalam, Hanna

مصطلحات موضوعية: Biochemistry and Molecular Biology, Biokemi och molekylärbiologi, mRNA degradation, metabolic labeling, nonsense-mediated decay, Major protease, SARS-CoV-2

الوصف: Nonsense mediated decay (NMD) is a pathway that regulates RNA turnover. Since its discovery, this pathway has been implicated in a variety of cellular processes ranging from differentiation to the restriction of viral replication. While NMD has been heavily studied since its discovery, the understanding of how the pathway carries out its function has been a long and convoluted process, where the current cornerstones that establish our present understanding of the regulatory mechanisms are continuously challenged. In this thesis, new methods were explored with the goal to provide tools that would simplify investigating the NMD pathway and potentially other pathways regulating RNA. We studied the use of nucleotide conversion methods and their applicability to yeast. Additionally, we designed a set of reporters that allow in vivo monitoring of NMD with an easy-to-read phenotype as an output. Moreover, we modified a reporter that was developed during the construction of the NMD reporters to also be applicable for alternative studies. In this particular case, we adapted one of our reporters to the study of the SARS-CoV-2 major protease (NSP5). Overall, simplified methods to interrogate cellular NMD were successfully constructed, in addition to establishing a sensitive yeast based system for the detection of anti-viral compounds.

الوصول الحر: https://gup.ub.gu.se/publication/333770Test

المؤلفون: Katarzyna Mikula, Katarzyna Chojnacka, Dawid Skrzypczak, Piotr Młynarz, Anna Witek-Krowiak

المصدر: Journal of Functional Foods
Journal of Functional Foods, Vol 73, Iss, Pp 104146-(2020)

مصطلحات موضوعية: 0301 basic medicine, GSH, Herbal extract from Gentianae Radix, 3CLpro, 3C-like protease, TCH, Herbal extract from Loranthi Ramus, FFA, Free fatty acid, IC50, 50% inhibitory concentrations, Covid-19, Coronavirus Disease 2019, Phytochemicals, CDC, Cholesterol-dependent cytolysin, Medicine (miscellaneous), Pharmacology, medicine.disease_cause, GCG, Gallocatechin gallate, Bioactivity, CTH, Herbal extract from Cassiae Semen, MNP, Marine Natural Product, chemistry.chemical_compound, DNA, Deoxyribonucleic acid, MERS-CoV, Middle East Respiratory Syndrome Coronavirus, Mpro, The major protease, Betulinic acid, TX341-641, DBM, Herbal extract from Dioscoreae Rhizoma, PLpro, The papain-like protease, Coronavirus, chemistry.chemical_classification, Nutrition and Dietetics, Chemistry, food and beverages, Biological activity, 04 agricultural and veterinary sciences, 040401 food science, EC50, 50% effective concentration, Pharmacophore, PLY, Pneumolysin, Article, WHO, World Health Organization, 03 medical and health sciences, 0404 agricultural biotechnology, SARS-CoV, Severe Acute Respiratory Syndrome coronavirus, ACE2, Angiotensin-converting enzyme 2, medicine, RNA, Ribonucleic acid, Antiviral, ComputingMethodologies_COMPUTERGRAPHICS, 030109 nutrition & dietetics, Pandemic, Nutrition. Foods and food supply, CBE, CBM, Herbal extracts from Rhizoma Cibotii, Polyphenols, Plant extracts, MTT test, Cytotoxicity test using 3- (4,5-dimethylthiazol-2-yl) −2,5-diphenyltetrazolium bromide, Enzyme, CC50, 50% cytotoxicity concentration, Viral replication, Polyphenol, FA, Fatty acid, Luteolin, CPE, Cytopathogenic effect, Food Science

الوصف: Graphical abstract
Highlights • Plant extracts are a source of phytochemicals useful in the treatment of coronavirus diseases. • The advantage of using natural plant extracts is their effectiveness and high safety for patients. • Water and ethanol plant extracts contain biologically active substances with antiviral activity. • Phytochemicals are natural inhibitors of viral enzymes.
The outbreak of Covid-19 disease caused by SARS-CoV-19, along with the lack of targeted medicaments and vaccines, forced the scientific world to search for new antiviral formulations. In this review, we describe the current knowledge about plant extracts containing polyphenols that inhibit Covid-19. Many plant-derived natural compounds (polyphenols) might provide a starting point for the research on the use of plant extracts in coronavirus treatment and prevention. Antivirus polyphenolic drugs can inhibit coronavirus enzymes, which are essential for virus replication and infection. This group of natural substances (betulinic acid, indigo, aloeemodine, luteolin, and quinomethyl triterpenoids, quercitin or gallates) is a potential key to designing antiviral therapies for inhibiting viral proteases. The known pharmacophore structures of bioactive substances can be useful in the elaboration of new anti-Covid-19 formulations. The benefit of using preparations containing phytochemicals is their high safety for patients and no side effects.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d14cee82201483e806e223697fbea2f9Test