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1.
Gut Microbes ; 14(1): 2105609, 2022.
Article in English | MEDLINE | ID: covidwho-1967793

ABSTRACT

The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.


Subject(s)
COVID-19 , Gastrointestinal Microbiome , Animals , Antiviral Agents/therapeutic use , Fatty Acids, Volatile , Male , Mammals/metabolism , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2
2.
Nat Commun ; 13(1): 4416, 2022 07 29.
Article in English | MEDLINE | ID: covidwho-1967601

ABSTRACT

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.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19/drug therapy , Cricetinae , Cytidine/analogs & derivatives , Ferrets , Humans , Hydroxylamines , Lung , Male
3.
DNA Cell Biol ; 41(8): 699-704, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1922165

ABSTRACT

The COVID-19 pandemic has highlighted the urgent need for the development of broad-spectrum antivirals to enhance preparedness against future spillover of zoonotic viruses with pandemic potential into the human population. Currently, the direct-acting orally available SARS-CoV-2 inhibitors molnupiravir and paxlovid are approved for human use under emergency use authorization. A promising next-generation therapeutic candidate is the orally available ribonucleoside analog 4'-fluorouridine (4'-FlU) that had potent antiviral efficacy against different viral targets, including SARS-CoV-2 in human organoids and animal models. Although a nucleoside analog inhibitor such as molnupiravir that targets the viral RNA-dependent RNA polymerase (RdRP) complex, 4'-FlU showed a distinct mechanism of activity, delayed chain termination, compared with molnupiravir's induction of viral error catastrophe. This review will focus on some currently approved and emerging medicines developed against SARS-CoV-2, examining their potential to form a pharmacological first-line defense against zoonotic viruses with pandemic potential.


Subject(s)
COVID-19 , Pandemics , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , SARS-CoV-2 , Uracil Nucleotides
4.
Science ; 375(6577): 161-167, 2022 Jan 14.
Article in English | MEDLINE | ID: covidwho-1648160

ABSTRACT

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and older adults. We describe 4'-fluorouridine (4'-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with high selectivity index in cells and human airway epithelia organoids. Polymerase inhibition within in vitro RNA-dependent RNA polymerase assays established for RSV and SARS-CoV-2 revealed transcriptional stalling after incorporation. Once-daily oral treatment was highly efficacious at 5 milligrams per kilogram (mg/kg) in RSV-infected mice or 20 mg/kg in ferrets infected with different SARS-CoV-2 variants of concern, initiated 24 or 12 hours after infection, respectively. These properties define 4'-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2, and related RNA virus infections.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Respiratory Syncytial Virus Infections/drug therapy , Respiratory Syncytial Virus, Human/drug effects , SARS-CoV-2/drug effects , Uracil Nucleotides/pharmacology , Administration, Oral , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/metabolism , COVID-19/virology , Cell Line , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Disease Models, Animal , Female , Ferrets , Humans , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Mononegavirales/drug effects , Mononegavirales/physiology , RNA-Dependent RNA Polymerase/metabolism , Respiratory Mucosa/virology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/genetics , Respiratory Syncytial Virus, Human/physiology , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Transcription, Genetic , Uracil Nucleotides/administration & dosage , Uracil Nucleotides/metabolism , Virus Replication/drug effects
5.
Nat Commun ; 12(1): 6415, 2021 11 05.
Article in English | MEDLINE | ID: covidwho-1503781

ABSTRACT

Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.


Subject(s)
Adenosine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19/drug therapy , Prodrugs/pharmacology , SARS-CoV-2/drug effects , Adenosine/pharmacology , Animals , COVID-19/metabolism , COVID-19/virology , Cell Line , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Female , Ferrets , Humans , SARS-CoV-2/isolation & purification
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