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Here, we show that sangivamycin is a potent antiviral against multiple variants of replicative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with half-maximal inhibitory concentration in the nanomolar range in several cell types. Sangivamycin suppressed SARS-CoV-2 replication with greater efficacy than remdesivir (another broad-spectrum nucleoside analog). When we investigated sangivamycin\u2019s potential for clinical administration, pharmacokinetic; absorption, distribution, metabolism, and excretion (ADME); and toxicity properties were found to be favorable. When tested in combination with remdesivir, efficacy was additive rather than competitive against SARS-CoV-2. The proven safety in humans, long half-life, potent antiviral activity (compared to remdesivir), and combinatorial potential suggest that sangivamycin is likely to be efficacious alone or in combination therapy to suppress viremia in patients. Sangivamycin may also have the ability to help combat drug-resistant or vaccine-escaping SARS-CoV-2 variants since it is antivirally active against several tested variants. Our results support the pursuit of sangivamycin for further preclinical and clinical development as a potential coronavirus disease 2019 therapeutic.<\/jats:p>","DOI":"10.1172\/jci.insight.153165","type":"journal-article","created":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T12:00:38Z","timestamp":1637582438000},"source":"Crossref","is-referenced-by-count":20,"title":["Sangivamycin is highly effective against SARS-CoV-2 in vitro and has favorable drug properties"],"prefix":"10.1172","volume":"7","author":[{"given":"Ryan P.","family":"Bennett","sequence":"first","affiliation":[{"name":"OyaGen, Inc., Rochester, New York, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena N.","family":"Postnikova","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brett P.","family":"Eaton","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingyun","family":"Cai","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuiqing","family":"Yu","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0724-7236","authenticated-orcid":true,"given":"Charles O.","family":"Smith","sequence":"additional","affiliation":[{"name":"Center for Musculoskeletal Research, University of Rochester School of Medicine & Dentistry, Rochester, New York, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janie","family":"Liang","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huanying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory A.","family":"Kocher","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harold C.","family":"Smith","sequence":"additional","affiliation":[{"name":"OyaGen, Inc., Rochester, New York, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7800-6045","authenticated-orcid":true,"given":"Jens H.","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Frederick, Maryland, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"232","published-online":{"date-parts":[[2022,1,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-0695-z"},{"key":"B2","unstructured":"World Health Organization. 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