Journal article
Structure-based phylogeny identifies Avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in mice
The Journal of clinical investigation, Vol.131(10), e147973
05/17/2021
DOI: 10.1172/JCI147973
PMID: 33844653
Abstract
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. We hypothesized that 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 named 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. 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, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, 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.
Details
- Title: Subtitle
- Structure-based phylogeny identifies Avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in mice
- Creators
- Young Joo Sun - Department of Ophthalmology, Stanford University, Palo Alto, United States of AmericaGabriel Velez - Department of Ophthalmology, Stanford University, Palo Alto, United States of AmericaDylan E Parsons - Department of Ophthalmology, Stanford University, Palo Alto, United States of AmericaKun Li - Department of Pediatrics, University of Iowa, Iowa City, United States of AmericaMiguel E Ortiz - Department of Pediatrics, University of Iowa, Iowa City, United States of AmericaShaunik Sharma - Department of Pediatrics, University of Iowa, Iowa City, United States of AmericaPaul B McCray Jr - Department of Pediatrics, University of Iowa, Iowa City, United States of AmericaAlexander G Bassuk - Department of Pediatrics, University of Iowa, Iowa City, United States of AmericaVinit B Mahajan - Department of Ophthalmology, Stanford University, Palo Alto, United States of America
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.131(10), e147973
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI147973
- PMID
- 33844653
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- name: NIH, award: P30DK-54759; name: NIH, award: P01AI060699; name: NHLBI/NIH, award: T32HL007638; name: NIH, award: R01EY024665; name: NIH, award: P30EY026877; name: NIH, award: F30EYE027986; name: NIH, award: T32GM007337; name: NEI/NIH, award: T32EY027816; DOI: 10.13039/100001818, name: Research to Prevent Blindness, award: N/A; DOI: 10.13039/501100007154, name: NIH, award: R01EY030151; name: NIH, award: R01EY031952; name: NIH, award: R01NS98950; name: Stanford ChEM-H/IMA, award: N/A
- Language
- English
- Electronic publication date
- 04/12/2021
- Date published
- 05/17/2021
- Academic Unit
- Neurology; Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Neurology (Pediatrics); Internal Medicine
- Record Identifier
- 9984071644402771
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