Coronaviruses (CoVs) traffic frequently between species resulting in novel disease outbreaks, most recently exemplified by the newly emerged SARS-CoV-2, the causative agent of COVID-19. Here, we show that the ribonucleoside analog β-d-N4-hydroxycytidine (NHC; EIDD-1931) has broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs, as well as increased potency against a CoV bearing resistance mutations to the nucleoside analog inhibitor remdesivir. In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β-d-N4-hydroxycytidine-5′-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.

Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in the genomes of RNA viruses during viral replication. β-D-N 4-hydroxycytidine (NHC, the initial metabolite of molnupiravir) is more than 100-fold more active than ribavirin or favipiravir against SARS-CoV-2, with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate that highly active mutagenic ribonucleosides may hold risk for the host.

FOM was common among patients with symptomatic KOA, and this could negatively impact physical activity. Psychological variables were significantly associated with FOM, suggesting behavioral and psychological interventions may decrease FOM and improve outcomes among individuals with symptomatic KOA.

153) 27Coronaviruses (CoVs) traffic frequently between species resulting in novel disease 28 outbreaks, most recently exemplified by the newly emerged SARS-CoV-2. Herein, we 29show that the ribonucleoside analog β-D-N 4 -hydroxycytidine (NHC, EIDD-1931) has 30 broad spectrum antiviral activity against SARS-CoV 2, MERS-CoV, and 31 . : bioRxiv preprint related zoonotic group 2b or 2c Bat-CoVs, as well as increased potency against a 32 coronavirus bearing resistance mutations to another nucleoside analog inhibitor. In 33 mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic 34 administration of EIDD-2801, an orally bioavailable hydroxycytidine-5'-isopropyl ester), improved pulmonary function, and reduced virus 36 titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were 37 associated with increased transition mutation frequency in viral but not host cell RNA, 38 supporting a mechanism of lethal mutagenesis. The potency of NHC/EIDD-2801 against 39 multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all 40 highlight its potential utility as an effective antiviral against SARS-CoV-2 and other 41 future zoonotic coronaviruses. 42 43 emergence, broadly active antivirals are clearly needed for rapid response to new CoV 63 outbreaks in humans and domesticated animals. 64Currently, there are no approved therapies specific for any human CoV. β-D-N4-65 hydroxycytidine (NHC, EIDD-1931) is orally bioavailable ribonucleoside analog with 66 broad-spectrum antiviral activity against various unrelated RNA viruses including 67 influenza, Ebola, CoV and Venezuelan equine encephalitis virus (VEEV) 10-13 . For VEEV, 68 the mechanism of action (MOA) for NHC has been shown to be through lethal 69 mutagenesis where deleterious transition mutations accumulate in viral RNA 11,14 . Here, 70we demonstrate that NHC exerts potent, broad-spectrum activity against SARS-CoV, 71 MERS-CoV and their related bat-CoV in primary human airway epithelial cell cultures 72 (HAE), a biologically relevant model of the human conducting airway. In addition, we 73 show that NHC is potently antiviral against the newly emerging SARS-CoV-2 as well as 74 against coronavirus bearing resistance mutations to the potent nucleoside analog 75 inhibitor, remdesivir (RDV). In SARS-or MERS-CoV infected mice, both prophylactic 76 and therapeutic administration EIDD-2801, an oral NHC-prodrug (b-D-N 4 -77 hydroxycytidine-5'-isopropyl ester) improved pulmonary function and reduced virus titer 78 and ameliorated disease severity. In addition, therapeutic EIDD-2801 reduced the 79 pathological features of ALI in SARS-CoV infected mice. Using a high-fidelity deep 80 sequencing approach (Primer ID), we found that increased mutation rates coincide with 81 decreased MERS-CoV yields in vitro and protective efficacy in vivo supporting the MOA 82 of lethal mutagenesis against emerging CoV 13 . The broad activity and therapeutic 83 efficacy of NHC/EIDD-2801 highlight its potential to diminish epidemic diseas...

BackgroundPhysical activity improves pain and function among individuals with knee osteoarthritis (OA), but most people with this condition are inactive. Physical therapists play a key role in helping people with knee OA to increase appropriate physical activity. However, health care access issues, financial constraints, and other factors impede some patients from receiving physical therapy (PT) for knee OA. A need exists to develop and evaluate other methods to provide physical activity instruction and support to people with knee OA. This study is examining the effectiveness of an internet-based exercise training (IBET) program designed for knee OA, designed by physical therapists and other clinicians.Methods/DesignThis is a randomized controlled trial of 350 participants with symptomatic knee OA, allocated to three groups: IBET, standard PT, and a wait list (WL) control group (in a 2:2:1 ratio, respectively). The study was funded by the Patient Centered Outcomes Research Institute, which conducted a peer review of the proposal. The IBET program provides patients with a tailored exercise program (based on functional level, symptoms, and current activity), video demonstrations of exercises, and guidance for appropriate exercise progression. The PT group receives up to 8 individual visits with a physical therapist, mirroring standard practice for knee OA and with an emphasis on a home exercise program. Outcomes are assessed at baseline, 4 months (primary time point) and 12 months (to assess maintenance of treatment effects). The primary outcome is the Western Ontario and McMaster Universities Osteoarthritis Index, and secondary outcomes include objective physical function, satisfaction with physical function, physical activity, depressive symptoms and global assessment of change. Linear mixed models will be used to compare both the IBET and standard PT groups to the WL control group, examine whether IBET is non-inferior to PT (a treatment that has an established evidence base for knee OA), and explore whether participant characteristics are associated with differential effects of IBET and/or standard PT. This research is in compliance with the Helsinki Declaration and was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill.DiscussionThe IBET program could be disseminated widely at relatively low cost and could be an important resource for helping patients with knee OA to adopt and maintain appropriate physical activity. This trial will provide an important evaluation of the effectiveness of this IBET program for knee OA.Trial registrationNCT02312713