ABSTRACT
Effective SARS-CoV-2 antiviral drugs are desperately needed. The SARS-CoV-2 main protease (Mpro) appears as an attractive target for drug development. We show that the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of ~6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro and found ~50 compounds with activity against Mpro. Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 ≤ 50 µM. Hits from our screen are enriched with hepatitis C NS3/4A protease targeting drugs including boceprevir, ciluprevir. narlaprevir, and telaprevir. This work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than boceprevir and suitable for rapid repurposing.
Subject(s)
Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Drug Evaluation, Preclinical , Drug Repositioning , Hepacivirus/drug effects , Hepatitis C/drug therapy , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Biological Assay , Fluorescence , High-Throughput Screening Assays , Humans , Reproducibility of ResultsABSTRACT
BACKGROUND: There is a growing understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) in the general population. The unique immunology of pregnancy may result in variations from the reported course of disease. CASE: A 27-year-old primigravid woman presented with mild COVID-19 symptoms at 28 2/7 weeks of gestation, testing positive for SARS-CoV-2 infection by nasopharyngeal swab reverse transcription-polymerase chain reaction (RT-PCR). Antibody seroconversion was detected at 36 6/7 weeks of gestation. She presented for delivery at 38 1/7 weeks of gestation, and her SARS-CoV-2 RT-PCR test result was positive. Severe acute respiratory syndrome coronavirus 2 RNA remained detectable 34 days postpartum and 104 days from her initial positive test. CONCLUSION: Prolonged viral shedding of SARS-CoV RNA may occur in the pregnant patient. If prevalent, this complicates the interpretation of a positive SARS-CoV-2 RT-PCR test result in the asymptomatic gravid patient.