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SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efficacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding in ferrets and prevented transmission. Pathogenicity in dwarf hamsters was VOC-dependent and highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four (gamma) orders of magnitude. Treatment effect size varied in individual dwarf hamsters infected with omicron and was significant in males, but not females. The dwarf hamster model recapitulates mixed efficacy of molnupiravir in human trials and alerts that benefit must be reassessed in vivo as VOC evolve. Molnupiravir was the first orally available SARS-CoV-2 antiviral approved for outpatient use against SARS-CoV-2, but its efficacy against variants of concern, especially delta, was questioned. Here the authors evaluate molnupiravir against variant of concern in numerous models, including human airway epithelium organoids, ferrets and Roborovski dwarf hamsters.

Therapeutic options against SARS-CoV-2 are underutilized. Two oral drugs, molnupiravir and paxlovid (nirmatrelvir/ritonavir), have received emergency use authorization. Initial trials suggested greater efficacy of paxlovid, but recent studies indicated comparable potency in older adults. Here, we compare both drugs in two animal models; the Roborovski dwarf hamster model for severe COVID-19-like lung infection and the ferret SARS-CoV-2 transmission model. Dwarf hamsters treated with either drug survive VOC omicron infection with equivalent lung titer reduction. Viral RNA copies in the upper respiratory tract of female ferrets receiving 1.25 mg/kg molnupiravir twice-daily are not significantly reduced, but infectious titers are lowered by >2 log orders and direct-contact transmission is stopped. Female ferrets dosed with 20 or 100 mg/kg nirmatrelvir/ritonavir twice-daily show 1–2 log order reduction of viral RNA copies and infectious titers, which correlates with low nirmatrelvir exposure in nasal turbinates. Virus replication resurges towards nirmatrelvir/ritonavir treatment end and virus transmits efficiently (20 mg/kg group) or partially (100 mg/kg group). Prophylactic treatment with 20 mg/kg nirmatrelvir/ritonavir does not prevent spread from infected ferrets, but prophylactic 5 mg/kg molnupiravir or 100 mg/kg nirmatrelvir/ritonavir block productive transmission. These data confirm reports of similar efficacy in older adults and inform on possible epidemiologic benefit of antiviral treatment. There is limited data on how SARS-CoV-2 antivirals compare regarding efficacy and blocking transmission. Here, treating dwarf hamsters and ferrets with either molnupiravir or paxlovid the authors find comparable efficacy against severe COVID-19-like disease and complete block of transmission by molnupiravir.

Alphaviruses including chikungunya virus (CHIKV) are mosquito-borne positive-strand RNA viruses that can cause various diseases in humans. Although compounds that inhibit CHIKV and other alphaviruses have been identified in vitro , there are no licensed antivirals against CHIKV. Here, we investigated a ribonucleoside analog, 4′-fluorouridine (4′-FlU), and demonstrated that it inhibited infectious virus production by several alphaviruses in vitro and reduced virus burden in mouse models of CHIKV and Mayaro virus infection. Our studies also indicated that 4′-FlU treatment reduced CHIKV-induced footpad swelling and reduced the production of pro-inflammatory cytokines. Inhibition in the mouse model correlated with effective oral delivery of 4′-FlU and accumulation of both 4′-FlU and its bioactive form in relevant tissues. In summary, 4′-FlU exhibits potential as a novel anti-alphavirus agent targeting the replication of viral RNA.

Re-emerging and emerging viral diseases, for which no approved vaccines or therapeutics exist, pose a significant public health threat in affected areas of the world. Antiviral drugs that are broadly active against multiple pathogenic viruses are much needed. Our findings demonstrating robust protection conferred by treatment with 4′-fluorouridine (4′-FlU) in viral infection models for Oropouche fever, Rift Valley fever, and severe fever with thrombocytopenia syndrome support the continuing development of this promising broad-spectrum antiviral drug candidate for the treatment of these notable viral diseases.

Nipah virus (NiV) is a zoonotic paramyxovirus with pandemic potential, for which no licensed vaccines or therapeutics for human use are available. The nucleoside analog 4′-fluorouridine (4′-FlU, EIDD-2749) has broad activity against RNA viruses including in vitro activity against the Malaysia and Bangladesh clades of NiV (NiV-M and NiV-B, respectively). Here, we report the pharmacokinetic profile of orally administered 4′-FlU in Syrian Golden hamsters and its efficacy against NiV-B. 4’-FlU was orally bioavailable and provided sustained exposure of its bioactive anabolite 4’-FlU 5’-triphosphate (4′-FlU-TP) in the brain. A 7-day treatment course after NiV infection delayed time to death. Extending treatment to 21–28 days reduced viremia, incidence of lung disease, lung lesion severity, inflammation, and mortality. Lesions, viral antigen, or viral RNA could be detected in some survivors, suggesting persistent infections. Sequence analysis of NiV populations showed nonsynonymous single-nucleotide variants (SNVs) in some brain specimens from 4′-FlU-treated animals. Amino acid changes occurred in the nucleocapsid, the polymerase, or the phosphoprotein. It is currently unclear whether they reduce viral susceptibility to treatment or impact virulence but caused a slight increase in 4′-FlU potency compared to the genetic parent virus in vitro . However, none of these SNVs increased viral fitness in human brain astrocytes. This study established proof-of-concept for efficacious oral treatment of lethal NiV infection with a small-molecule nucleoside analog inhibitor in a relevant animal model.

Adenoviruses (Ads) cause a wide array of end-organ and disseminated diseases in severely immunosuppressed patients. For example, [almost equal to]20% of pediatric allogeneic hematopoietic stem cell transplant recipients develop disseminated Ad infection, and the disease proves fatal in as many as 50-80% of these patients. Ad infections are a serious problem for solid-organ transplant recipients and AIDS patients as well. Unfortunately, there are no antiviral drugs approved specifically to treat these infections. A suitable animal model that is permissive for Ad replication would help in the discovery process. Here we identify an animal model to study Ad pathogenesis and the efficacy of antiviral compounds. We show that human serotype 5 Ad (Ad5) causes severe systemic disease in immunosuppressed Syrian hamsters that is similar to that seen in immunocompromised patients. We also demonstrate that hexadecyloxypropyl-cidofovir (CMX001) rescues the hamsters from a lethal challenge with Ad5. The antiviral drug provided protection both prophylactically and when given up to 2 days after i.v. exposure to Ad5. CMX001 acts by reducing Ad replication in key target organs. Thus, the immunosuppressed Syrian hamster is a powerful model to evaluate anti-Ad drugs, and its use can facilitate the entry of drugs such as CMX001 into clinical trials.

CMX001, an orally active lipid conjugate of cidofovir, is 50 times more active in vitro against herpes simplex virus (HSV) replication than acyclovir or cidofovir. These studies compared the efficacy of CMX001 to acyclovir in BALB/c mice inoculated intranasally with HSV types 1 or 2. CMX001 was effective in reducing mortality using doses of 5 to 1.25 mg/kg administered orally once daily, even when treatments were delayed 48–72 h post viral inoculation. Organ samples obtained from mice treated with CMX001 had titers 3–5 log10 plaqueforming units per gram of tissue lower than samples obtained from mice treated with acyclovir, including 5 different regions of the brain. Detectable concentrations of drug-related radioactivity were documented in the central nervous system of mice after oral administration of 14C-CMX001. These studies indicate that CMX001 penetrates the blood-brain barrier, is a potent inhibitor of HSV replication in disseminated infections and central nervous system infections, and is superior to acyclovir.

Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4’-Fluorouridine (4’-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus (RSV), we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium (HAE) models, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4’-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar to sub-micromolar potency in HAE cells. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4’-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4’-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1)pdm09 (pdmCa09) with 4’-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating a broad time window for effective intervention. Therapeutic oral 4’-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pdmCa09. Recoverees were protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4’-FlU and supports 4’-FlU as developmental candidate for the treatment of seasonal and pandemic influenza.

Smallpox was eradicated by the World Health Organization (WHO) vaccination campaign in the 1970s and the variola virus was restricted to repositories in the United States and Russia. Recently, however, concerns have arisen about the possible existence of variola outside these sites and the potential for using the virus as a weapon of bioterror. The world population now has little residual immunity to smallpox and supplies of the smallpox vaccine are being reconstituted. Large numbers of individuals with various skin diseases or immunosuppression owing to AIDS or organ transplantation medications, or who are pregnant or have heart disease might not be ideal candidates for vaccination with the current live vaccines. It would be useful to have an orally active drug that could be self-administered in case of an outbreak of smallpox.

Viral infections, such as Ebola, severe acute respiratory syndrome/Middle East respiratory syndrome and West Nile virus have emerged as a serious health threat with no effective therapies. These infections have little commercial potential and are not a high priority for the pharmaceutical industry. However, the academic community has been active in this area for many years. The challenge is how to take this academic virology knowledge into a drug discovery and development domain. One approach is the use of consortia and public-private partnerships - this article highlights ongoing efforts in the USA. Public funds, such as those from government sources, can support research efforts that do not to appear to have commercial value. The key to success is finding a way to combine the different cultural and operational values and reward systems into a productive collaboration to identify new antivirals.