molnupiravir and Disease-Models--Animal

Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients.. We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds.. When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination.. Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19.. stated in the acknowledgment.

Topics: Amides; Animals; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Cytidine; Disease Models, Animal; Drug Therapy, Combination; Female; Hydroxylamines; Lung; Mesocricetus; Pyrazines; RNA, Viral; Treatment Outcome; Viral Load

The COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication is observed in animals when the drug is administered either beginning 12 h before or 12 h following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients.

Topics: Administration, Oral; Animals; Antiviral Agents; Chlorocebus aethiops; COVID-19; COVID-19 Drug Treatment; Cytidine; Disease Models, Animal; Humans; Hydroxylamines; Mesocricetus; SARS-CoV-2; Vero Cells; Virus Replication

Coronavirus Disease 2019 (Covid-19) continues to challenge the limits of our knowledge and our healthcare system. Here we sought to define the host immune response, a.k.a, the "cytokine storm" that has been implicated in fatal COVID-19 using an AI-based approach.. Over 45,000 transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature using ACE2 as a 'seed' gene; ACE2 was rationalized because it encodes the receptor that facilitates the entry of SARS-CoV-2 (the virus that causes COVID-19) into host cells. An AI-based approach was used to explore the utility of the signature in navigating the uncharted territory of Covid-19, setting therapeutic goals, and finding therapeutic solutions.. The 166-gene signature was surprisingly conserved across all viral pandemics, including COVID-19, and a subset of 20-genes classified disease severity, inspiring the nomenclatures ViP and severe-ViP signatures, respectively. The ViP signatures pinpointed a paradoxical phenomenon wherein lung epithelial and myeloid cells mount an IL15 cytokine storm, and epithelial and NK cell senescence and apoptosis determine severity/fatality. Precise therapeutic goals could be formulated; these goals were met in high-dose SARS-CoV-2-challenged hamsters using either neutralizing antibodies that abrogate SARS-CoV-2•ACE2 engagement or a directly acting antiviral agent, EIDD-2801. IL15/IL15RA were elevated in the lungs of patients with fatal disease, and plasma levels of the cytokine prognosticated disease severity.. The ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool to rapidly assess disease severity and vet candidate drugs.. This work was supported by the National Institutes for Health (NIH) [grants CA151673 and GM138385 (to DS) and AI141630 (to P.G), DK107585-05S1 (SD) and AI155696 (to P.G, D.S and S.D), U19-AI142742 (to S.. Cooperative Centers for Human Immunology)]; Research Grants Program Office (RGPO) from the University of California Office of the President (UCOP) (R00RG2628 & R00RG2642 to P.G, D.S and S.D); the UC San Diego Sanford Stem Cell Clinical Center (to P.G, D.S and S.D); LJI Institutional Funds (to S.C); the VA San Diego Healthcare System Institutional funds (to L.C.A). GDK was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists.. The host immune response in COVID-19.

Topics: Angiotensin-Converting Enzyme 2; Animals; Antibodies, Neutralizing; Antiviral Agents; Artificial Intelligence; Autopsy; COVID-19; COVID-19 Drug Treatment; Cricetinae; Cytidine; Databases, Genetic; Disease Models, Animal; Gene Expression Profiling; Gene Regulatory Networks; Genetic Markers; Humans; Hydroxylamines; Interleukin-15; Lung; Mesocricetus; Pandemics; Receptors, Interleukin-15; Virus Diseases

The emergence of SARS-CoV-2 variants of concern (VoCs) has exacerbated the COVID-19 pandemic. Currently available monoclonal antibodies and vaccines appear to have reduced efficacy against some of these VoCs. Antivirals targeting conserved proteins of SARS-CoV-2 are unlikely to be affected by mutations arising in VoCs and should therefore be effective against emerging variants. We here investigate the efficacy of molnupiravir, currently in phase 2 clinical trials, in hamsters infected with Wuhan strain or B.1.1.7 and B.1.351 variants. Molnupiravir proved to be effective against infections with each of the variants and therefore may have potential combating current and future emerging VoCs.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibodies, Viral; Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Cricetinae; Cytidine; Disease Models, Animal; Female; Hydroxylamines; Mutation; Pandemics; SARS-CoV-2; Virus Replication

Topics: Animals; Antiviral Agents; Cytidine; Disease Models, Animal; Drug Resistance, Viral; Humans; Hydroxylamines; Influenza, Human; Macaca; Ribonucleosides

Seasonal influenza viruses cause major morbidity and mortality worldwide, threatening in particular older adults and the immunocompromised. Two classes of influenza therapeutics dominate current disease management, but both are compromised by pre-existing or rapidly emerging viral resistance. We have recently reported a novel ribonucleoside analog clinical candidate, EIDD-2801, that combines potent antiviral efficacy in ferrets and human airway epithelium cultures with a high barrier against viral escape. In this study, we established fundamental EIDD-2801 efficacy paradigms against pandemic and seasonal influenza A virus (IAV) strains in ferrets that can be used to inform exposure targets and treatment regimens. Based on reduction of shed virus titers, alleviation of clinical signs, and lowered virus burden in upper and lower respiratory tract tissues, lowest efficacious oral dose concentrations of EIDD-2801, given twice daily, were 2.3 and 7 mg/kg of body weight against seasonal and pandemic IAVs, respectively. The latest opportunity for initiation of efficacious treatment was 36 hours after infection of ferrets. Administered in 12-hour intervals, three 7 mg/kg doses of EIDD-2801 were sufficient for maximal therapeutic benefit against a pandemic IAV and significantly shortened the time to resolution of clinical signs. Ferrets infected with pandemic IAV and treated following the minimally efficacious EIDD-2801 regimen demonstrated significantly less shed virus and inflammatory cellular infiltrates in nasal lavages, but mounted a robust humoral antiviral response after recovery that was indistinguishable from that of vehicle-treated animals. These results provide an experimental basis in a human disease-relevant influenza animal model for clinical testing of EIDD-2801.

Topics: Animals; Antiviral Agents; Cytidine; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Resistance, Viral; Ferrets; HEK293 Cells; Humans; Hydroxylamines; Influenza A virus; Influenza, Human; Madin Darby Canine Kidney Cells; Mutation; Ribonucleosides

Topics: Adenosine Monophosphate; Alanine; Animals; Antibiotic Prophylaxis; Antiviral Agents; Betacoronavirus; Cell Line; Coronavirus Infections; COVID-19; Cytidine; Disease Models, Animal; Drug Resistance, Viral; Humans; Hydroxylamines; Lung; Mice; Mice, Inbred C57BL; Middle East Respiratory Syndrome Coronavirus; Models, Molecular; Mutation; Pandemics; Pneumonia, Viral; Primary Cell Culture; Random Allocation; Respiratory System; Ribonucleosides; RNA-Dependent RNA Polymerase; RNA, Viral; SARS-CoV-2; Virus Replication