PT  - JOURNAL ARTICLE
AU  - Joo Sun, Young
AU  - Velez, Gabriel
AU  - Parsons, Dylan
AU  - Li, Kun
AU  - Ortiz, Miguel
AU  - Sharma, Shaunik
AU  - McCray, Paul B.
AU  - Bassuk, Alexander G.
AU  - Mahajan, Vinit B.
TI  - TMPRSS2 structure-phylogeny repositions Avoralstat for SARS-CoV-2 prophylaxis in mice
AID  - 10.1101/2021.01.04.425289
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.04.425289
4099  - http://biorxiv.org/content/early/2021/01/04/2021.01.04.425289.short
4100  - http://biorxiv.org/content/early/2021/01/04/2021.01.04.425289.full
AB  - Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target.1–3 We hypothesized drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo.4,5 Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor,6 inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle,5 Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans.Competing Interest StatementThe authors have declared no competing interest.