A thiol-saccharide therapy to treat COVID-19

NIH Pandemic-Era Grants

Pandemic Era Grants

2020

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Principal Investigator: John V Fahy
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2020
Award: $768,543
Funding agency: National Heart Lung and Blood Institute

ABSTRACT COVID19 is causing an unprecedented global health emergency worldwide and new treatments are urgently needed. In this grant application we propose to determine the therapeutic utility of MUC-031 - a dithiol modified saccharide - as a treatment for COVID19. We are currently developing MUC-031 as a novel mucolytic based on its ability to cleave disulfide crosslinks between mucin polymers in mucus gels. These cystine linkages confer stiffness and rigidity to pathologic mucus gels. Cystines also have roles in maintaining the native binding interface in the receptor binding domain (RBD) of the SARS-CoV2 spike (S) protein (SARS-2-S), which binds ACE2 on host cells as an entry receptor. We hypothesize that cleavage of cystines in SARS-2-S will alter the native conformation of the RBD and disable SARS-2-S binding to ACE2. In preliminary data in a plate-binding assay, we find that MUC-031 is highly potent in inhibiting SAR-2-S binding to ACE2 and effective in preventing SARS- CoV2 pseudovirions from infecting lung epithelial cells. We propose two aims to quickly generate further data to support MUC-031 as a novel treatment for COVID19. AIM 1 will determine if MUC-031 disables SARS-2-S in vitro to inhibit SARS-CoV2 infection. In this Aim we will use a plate binding assay and cell culture systems to determine the dose and time determinants of MUC-031 inhibition of SARS-2-S binding to ACE2 and SARS-CoV2 infection of cells. AIM 2 will determine if MUC-031 improves COVID19 outcomes in vivo. Here we will use a Syrian hamster model of COVID19 based on recent publication of the utility of this model for COVID19 research. Together our aims will quickly determine if MUC-031 has therapeutic utility in COVID19. Our proposal leverages work in an existing tPPG and holds promise to yield a novel treatment in a relatively short timeframe. The mechanism of MUC-031 proposed here is distinct from that of all other anti-viral therapies being tested, and will add to the arsenal of treatments to stop the pandemic.

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