RT Journal Article
SR Electronic
T1 TMPRSS2 structure-phylogeny repositions Avoralstat for SARS-CoV-2 prophylaxis in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.04.425289
DO 10.1101/2021.01.04.425289
A1 Joo Sun, Young
A1 Velez, Gabriel
A1 Parsons, Dylan
A1 Li, Kun
A1 Ortiz, Miguel
A1 Sharma, Shaunik
A1 McCray, Paul B.
A1 Bassuk, Alexander G.
A1 Mahajan, Vinit B.
YR 2021
UL http://biorxiv.org/content/early/2021/01/04/2021.01.04.425289.abstract
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.