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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.
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
4.
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
5.
Nat Microbiol ; 6(1): 11-18, 2021 01.
Article in English | MEDLINE | ID: covidwho-1387364

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6-9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/prevention & control , COVID-19/transmission , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , COVID-19/immunology , Chlorocebus aethiops , Cytidine/pharmacology , Cytokines/immunology , Disease Models, Animal , Disease Transmission, Infectious/prevention & control , Female , Ferrets , Random Allocation , Vero Cells
6.
Curr Opin Virol ; 49: 127-138, 2021 08.
Article in English | MEDLINE | ID: covidwho-1252630

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has had a catastrophic impact on human health and the world economy. The response of the scientific community was unparalleled, and a combined global effort has resulted in the creation of vaccines in a shorter time frame than previously unimaginable. Reflecting this concerted effort, the structural analysis of the etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has progressed with an unprecedented pace. Since the onset of the pandemic, over 1000 high-resolution structures of a broad range of SARS-CoV-2 proteins have been solved and made publicly available. These structures have aided in the identification of numerous potential druggable targets and have contributed to the design of different vaccine candidates. This opinion article will discuss the impact of high-resolution structures in understanding SARS-CoV-2 biology and explore their role in the development of vaccines and antivirals.


Subject(s)
COVID-19/prevention & control , SARS-CoV-2/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology
7.
PLoS Pathog ; 17(2): e1009371, 2021 02.
Article in English | MEDLINE | ID: covidwho-1138592

ABSTRACT

Morbilliviruses, such as measles virus (MeV) and canine distemper virus (CDV), are highly infectious members of the paramyxovirus family. MeV is responsible for major morbidity and mortality in non-vaccinated populations. ERDRP-0519, a pan-morbillivirus small molecule inhibitor for the treatment of measles, targets the morbillivirus RNA-dependent RNA-polymerase (RdRP) complex and displayed unparalleled oral efficacy against lethal infection of ferrets with CDV, an established surrogate model for human measles. Resistance profiling identified the L subunit of the RdRP, which harbors all enzymatic activity of the polymerase complex, as the molecular target of inhibition. Here, we examined binding characteristics, physical docking site, and the molecular mechanism of action of ERDRP-0519 through label-free biolayer interferometry, photoaffinity cross-linking, and in vitro RdRP assays using purified MeV RdRP complexes and synthetic templates. Results demonstrate that unlike all other mononegavirus small molecule inhibitors identified to date, ERDRP-0519 inhibits all phosphodiester bond formation in both de novo initiation of RNA synthesis at the promoter and RNA elongation by a committed polymerase complex. Photocrosslinking and resistance profiling-informed ligand docking revealed that this unprecedented mechanism of action of ERDRP-0519 is due to simultaneous engagement of the L protein polyribonucleotidyl transferase (PRNTase)-like domain and the flexible intrusion loop by the compound, pharmacologically locking the polymerase in pre-initiation conformation. This study informs selection of ERDRP-0519 as clinical candidate for measles therapy and identifies a previously unrecognized druggable site in mononegavirus L polymerase proteins that can silence all synthesis of viral RNA.


Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Measles virus/drug effects , Measles/drug therapy , Morpholines/pharmacology , Piperidines/pharmacology , Pyrazoles/pharmacology , RNA, Viral/biosynthesis , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Animals , Chlorocebus aethiops , Measles/metabolism , Measles/virology , Measles virus/enzymology , Mutation , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , Vero Cells
8.
Res Sq ; 2020 Oct 12.
Article in English | MEDLINE | ID: covidwho-869428

ABSTRACT

The COVID-19 pandemic is having a catastrophic impact on human health. Widespread community transmission has triggered stringent distancing measures with severe socioeconomic consequences. Gaining control of the pandemic will depend on interruption of transmission chains until protective herd immunity arises. Ferrets and related members of the weasel genus transmit SARS-CoV-2 efficiently with minimal clinical signs, resembling spread in the young-adult population. We previously reported an orally efficacious nucleoside analog inhibitor of influenza viruses, EIDD-2801 (or MK-4482), that was repurposed against SARS-CoV-2 and is in phase II/III clinical trials. Employing the ferret model, we demonstrate in this study high SARS-CoV-2 burden in nasal tissues and secretions that coincides with efficient direct-contact transmission. Therapeutic treatment of infected animals with twice-daily MK-4482/EIDD-2801 significantly reduced upper respiratory tract SARS-CoV-2 load and completely suppressed spread to untreated contact animals. This study identifies oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.

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