المؤلفون: McMillan, Rachel, Lo, Michael, Zhang, Xing-Quan, Beadle, James, Valiaeva, Nadejda, Garretson, Aaron, Clark, Alex, Freshman, Jon, Murphy, Joyce, Montgomery, Joel, Spiropoulou, Christina, Schooley, Robert, Hostetler, Karl, Carlin, Aaron

مصطلحات موضوعية: Antiviral agents, Broad spectrum antiviral, Ebola virus, Filovirus, Flavivirus, GS-441524, GS-5734, Hemorrhagic fever viruses, Hendra virus, Henipavirus, Human coronavirus 229E, Lipid prodrugs, Nipah virus, Paramyxovirus, Pneumovirus, RNA virus, Remdesivir, Remdesivir nucleoside, Respiratory syncytial virus, Respiratory viruses, V2043, Zika virus, dengue virus, Antiviral Agents, Prodrugs, Nucleosides, Glycerol, Lipids

الوصف: Broad spectrum oral antivirals are urgently needed for the early treatment of many RNA viruses of clinical concern. We previously described the synthesis of 1-O-octadecyl-2-O-benzyl-glycero-3-phospho-RVn (V2043), an orally bioavailable lipid prodrug of remdesivir nucleoside (RVn, GS-441524) with broad spectrum antiviral activity against viruses with pandemic potential. Here we compared the relative activity of V2043 with new RVn lipid prodrugs containing sn-1 alkyl ether or sn-2 glycerol modifications. We found that 3-F-4-MeO-Bn, 3-CN-Bn, and 4-CN-Bn sn-2 glycerol modifications improved antiviral activity compared to V2043 when tested in vitro against clinically important RNA viruses from 5 virus families. These results support the continued development of V2043 and sn-2 glycerol modified RVn lipid prodrugs for the treatment of a broad range of RNA viruses for which there are limited therapies.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5nd4m9f8Test

المؤلفون: Carlin, Aaron F, Beadle, James R, Clark, Alex E, Gully, Kendra L, Moreira, Fernando R, Baric, Ralph S, Graham, Rachel L, Valiaeva, Nadejda, Leibel, Sandra L, Bray, William, McMillan, Rachel E, Freshman, Jonathan E, Garretson, Aaron F, McVicar, Rachael N, Rana, Tariq, Zhang, Xing-Quan, Murphy, Joyce A, Schooley, Robert T, Hostetler, Karl Y

المصدر: Journal of Medicinal Chemistry. 66(8)

مصطلحات موضوعية: Lung, Prevention, Emerging Infectious Diseases, Infectious Diseases, Infection, Animals, Mice, Antiviral Agents, SARS-CoV-2, COVID-19, Phospholipids, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry

الوصف: Early antiviral treatments, including intravenous remdesivir (RDV), reduce hospitalization and severe disease caused by COVID-19. An orally bioavailable RDV analog may facilitate earlier treatment of non-hospitalized COVID-19 patients. Here we describe the synthesis and evaluation of alkyl glyceryl ether phosphodiesters of GS-441524 (RVn), lysophospholipid analogs which allow for oral bioavailability and stability in plasma. Oral treatment of SARS-CoV-2-infected BALB/c mice with 1-O-octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-RVn (60 mg/kg orally, once daily for 5 days starting 12h after infection) reduced lung viral load by 1.5 log10 units versus vehicle at day 2 and to below the limit of detection at day 5. Structure/activity evaluation of additional analogs that have hydrophobic ethers at the sn-2 of glycerol revealed improved in vitro antiviral activity by introduction of a 3-fluoro-4-methoxy-substituted benzyl or a 3- or 4-cyano-substituted benzyl. Collectively, our data support the development of RVn phospholipid prodrugs as oral antiviral agents for prevention and treatment of SARS-CoV-2 infections.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9vh4n42sTest

المؤلفون: Schooley, Robert T, Carlin, Aaron F, Beadle, James R, Valiaeva, Nadejda, Zhang, Xing-Quan, Clark, Alex E, McMillan, Rachel E, Leibel, Sandra L, McVicar, Rachael N, Xie, Jialei, Garretson, Aaron F, Smith, Victoria I, Murphy, Joyce, Hostetler, Karl Y

مصطلحات موضوعية: Prevention, Biodefense, Rare Diseases, Stem Cell Research, Infectious Diseases, Vaccine Related, Lung, Emerging Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, SARS-CoV-2, remdesivir, remdesivir nucleoside, antiviral agents, lipid prodrugs, Vero E6 cells, Calu-3 cells, Caco-2 cells, Huh7.5 cells, PSC-derived human lung cells, Huh7.5 cells and PSC-derived human lung cells, Remdesivir, Remdesivir nucleoside, Microbiology, Medical Microbiology, Pharmacology and Pharmaceutical Sciences

الوصف: Remdesivir (RDV, GS-5734) is currently the only FDA-approved antiviral drug for the treatment of SARS CoV-2 infection. The drug is approved for use in adults or children 12-years or older who are hospitalized for the treatment of COVID-19 on the basis of an acceleration of clinical recovery for inpatients with this disease. Unfortunately, the drug must be administered intravenously, restricting its use to those requiring hospitalization for relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. Potent orally bioavailable antiviral drugs for early treatment of SARS-CoV-2 infection are urgently needed and several including molnupiravir and PF-07321332 are currently in clinical development. We focused on making simple, orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single-step intracellular cleavage. In addition to high oral bioavailability, stability in plasma and simpler metabolic activation, new oral lipid prodrugs of RVn had submicromolar anti-SARS-CoV-2 activity in a variety of cell types including Vero E6, Calu-3, Caco-2, human pluripotent stem cell (PSC)-derived lung cells and Huh7.5 cells. In Syrian hamsters oral treatment with ODBG-P-RVn was well tolerated and achieved therapeutic levels in plasma above the EC90 for SARS-CoV-2. The results suggest further evaluation as an early oral treatment for SARS-CoV-2 infection to minimize severe disease and reduce hospitalizations.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/26s204w3Test

المؤلفون: Beadle, James R, Aldern, Kathy A, Zhang, Xing-Quan, Valiaeva, Nadejda, Hostetler, Karl Y, Schooley, Robert T

مصطلحات موضوعية: Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Infectious Diseases, HIV/AIDS, Prevention, Infection, Adenine, Chemistry Techniques, Synthetic, Esters, Humans, Molecular Structure, Organophosphates, Tenofovir, Tissue Distribution, HIV-1 prophylaxis, Long-acting antiretroviral, Adherence, Microbiology, Pharmacology and Pharmaceutical Sciences, Virology, Medical microbiology, Pharmacology and pharmaceutical sciences

الوصف: Pre-exposure prophylaxis (PrEP) with topically or systemically administered antiretroviral agents can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials using tenofovir-containing agents, HIV-1 acquisition is reduced but not eliminated. Incomplete adherence remains the major contributor to failure. Sustained release or long-acting antiretroviral agents may provide better HIV-1 protection by reducing the clinical impact of incomplete adherence. To reduce dosing frequency, we synthesized a novel tenofovir prodrug, octadecyloxyethyl benzyl tenofovir (ODE-Bn-TFV), that is designed to release TFV slowly in tissues, and showed potent anti-HIV activity in vitro (EC50 = 1.7 nM). In cells exposed to 14C labeled TFV, ODE-Bn-TFV or the quickly activated monoester ODE-TFV, rapid cellular uptake for both lipophilic analogs was noted, achieving 50-fold higher levels than unmodified TFV after 48 h. Following exposure to ODE-[8-14C]TFV, the intracellular diphosphate levels were approximately four-fold higher than with ODE-Bn-TFV. However, intracellular TFVpp drug levels fell rapidly yielding a half-life of about two days. TFVpp levels in ODE-Bn-TFV treated cells decreased much more slowly and reached half-maximal levels in about seven days. These results suggest early accumulation of ODE-Bn-TFV followed by sustained intracellular release following cleavage of the ester bonds linking the ODE and benzyl moieties to the active molecular precursor, thereby potentially allowing for less frequent administration than with more rapidly activated forms of tenofovir.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/7xq316mkTest

المؤلفون: Zhu, Siyu, Zhang, Chaozai, Huang, Lina S, Zhang, Xing-Quan, Xu, Yan, Fang, Xiong, Zhou, Jiao, Wu, Meixian, Schooley, Robert T, Huang, Ziwei, An, Jing

المصدر: Molecules (Basel, Switzerland). 24(8)

مصطلحات موضوعية: Cell Line, Animals, Humans, RNA Helicases, Viral Nonstructural Proteins, Antiviral Agents, Structure-Activity Relationship, Computer Simulation, Cricetinae, Drug Discovery, Molecular Docking Simulation, Zika Virus, Zika Virus Infection, Zika virus, benzenediol, flaviviruses, non-structural protein 3, structure-based virtual screening, tetrahydroxy pentanoate, Medicinal and Biomolecular Chemistry, Organic Chemistry, Theoretical and Computational Chemistry

الوصف: Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain-Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC50 values at the micro-molar level (8.5 μM and 15.2 μM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure-activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/94f5301nTest

المؤلفون: Zhang, Chaozai, Zhang, Huijun, Huang, Lina S, Zhu, Siyu, Xu, Yan, Zhang, Xing-Quan, Schooley, Robert T, Yang, Xiaohong, Huang, Ziwei, An, Jing

المصدر: Molecules (Basel, Switzerland). 23(11)

مصطلحات موضوعية: Cell Line, Humans, HIV-1, Anti-HIV Agents, Drug Evaluation, Preclinical, Computational Biology, Binding Sites, Molecular Structure, Protein Binding, Quantitative Structure-Activity Relationship, Drug Design, Models, Molecular, Computer Simulation, Virus Internalization, Molecular Docking Simulation, CD4 Antigens, 3D-QSAR, CD4, entry inhibitor, virtual screening, Medicinal and Biomolecular Chemistry, Organic Chemistry, Theoretical and Computational Chemistry

الوصف: Human immunodeficiency virus type 1 (HIV-1) is responsible for the majority of HIV infections worldwide, and we still lack a cure for this infection. Blocking the interaction of HIV-1 and its primary receptor CD4 is one strategy for identifying new anti-HIV-1 entry inhibitors. Here we report the discovery of a novel ligand that can inhibit HIV-1 entry and infection via CD4. Biological and computational analyses of this inhibitor and its analogs, using bioactivity evaluation, Rule of Five (RO5), comparative molecular field analysis (CoMFA)/comparative molecular similarity index analysis (CoMSIA) models, and three-dimensional quantitative structure-activity relationship (3D-QSAR), singled out compound 3 as a promising lead molecule for the further development of therapeutics targeting HIV-1 entry. Our study demonstrates an effective approach for employing structure-based, rational drug design techniques to identify novel antiviral compounds with interesting biological activities.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/91v3w803Test

المؤلفون: McMillan, Rachel E., Lo, Michael K., Zhang, Xing-Quan, Beadle, James R., Valiaeva, Nadejda, Garretson, Aaron F., Clark, Alex E., Freshman, Jon E., Murphy, Joyce, Montgomery, Joel M., Spiropoulou, Christina F., Schooley, Robert T., Hostetler, Karl Y., Carlin, Aaron F.

المساهمون: Bill and Melinda Gates Foundation, National Institutes of Health, NIGMS, NIAID, Burroughs Wellcome Fund

المصدر: Antiviral Research ; volume 219, page 105718 ; ISSN 0166-3542

مصطلحات موضوعية: Virology, Pharmacology

الإتاحة: https://doi.org/10.1016/j.antiviral.2023.105718Test
https://api.elsevier.com/content/article/PII:S0166354223001961?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0166354223001961?httpAccept=text/plainTest

المؤلفون: Zhang, Huijun, Zhang, Xing-Quan, Huang, Lina S., Fang, Xiong, Khan, Mohsin, Xu, Yan, An, Jing, Schooley, Robert T., Huang, Ziwei

المساهمون: University of California, San Diego

المصدر: Biochemistry and Biophysics Reports ; volume 30, page 101283 ; ISSN 2405-5808

مصطلحات موضوعية: Biochemistry, Biophysics

الإتاحة: https://doi.org/10.1016/j.bbrep.2022.101283Test
https://api.elsevier.com/content/article/PII:S2405580822000838?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2405580822000838?httpAccept=text/plainTest

المؤلفون: Li, Yue-qi, Zhai, Heng, Ye, Ping, Zhang, Xing-quan, Guo, Chang-ping

المساهمون: Southwest University of Science and Technology

المصدر: Defence Technology ; volume 18, issue 5, page 855-861 ; ISSN 2214-9147

مصطلحات موضوعية: Metals and Alloys, Mechanical Engineering, Ceramics and Composites, Computational Mechanics

الإتاحة: https://doi.org/10.1016/j.dt.2021.05.006Test
https://api.elsevier.com/content/article/PII:S2214914721000842?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2214914721000842?httpAccept=text/plainTest

المؤلفون: Chen, Hui-Wen, Liu, Pei-Feng, Liu, Yu-Tsueng, Kuo, Sherwin, Zhang, Xing-Quan, Schooley, Robert T, Rohde, Holger, Gallo, Richard L, Huang, Chun-Ming

المصدر: Scientific reports. 6(1)

مصطلحات موضوعية: Nasal Cavity, Chick Embryo, Animals, Staphylococcus aureus, Bacterial Proteins, Carrier Proteins, Influenza A Virus, H1N1 Subtype, Microbiota, Influenza A Virus, H1N1 Subtype, Vaccine Related, Prevention, Emerging Infectious Diseases, Infectious Diseases, Influenza, Pneumonia & Influenza, Biodefense, 2.2 Factors relating to physical environment, 2.1 Biological and endogenous factors, Infection, Biochemistry and Cell Biology, Other Physical Sciences

الوصف: Several microbes, including Staphylococcus epidermidis (S. epidermidis), a Gram-positive bacterium, live inside the human nasal cavity as commensals. The role of these nasal commensals in host innate immunity is largely unknown, although bacterial interference in the nasal microbiome may promote ecological competition between commensal bacteria and pathogenic species. We demonstrate here that S. epidermidis culture supernatants significantly suppressed the infectivity of various influenza viruses. Using high-performance liquid chromatography together with mass spectrometry, we identified a giant extracellular matrix-binding protein (Embp) as the major component involved in the anti-influenza effect of S. epidermidis. This anti-influenza activity was abrogated when Embp was mutated, confirming that Embp is essential for S. epidermidis activity against viral infection. We also showed that both S. epidermidis bacterial particles and Embp can directly bind to influenza virus. Furthermore, the injection of a recombinant Embp fragment containing a fibronectin-binding domain into embryonated eggs increased the survival rate of virus-infected chicken embryos. For an in vivo challenge study, prior Embp intranasal inoculation in chickens suppressed the viral titres and induced the expression of antiviral cytokines in the nasal tissues. These results suggest that S. epidermidis in the nasal cavity may serve as a defence mechanism against influenza virus infection.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2v15v2z8Test