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Principal Investigator: ASHLEY M. DEACON
Organization: ACCELERO BIOSTRUCTURES, INC.
Fiscal Year: 2020
Award: $486,536
Funding agency: National Institute of General Medical Sciences
The novel SARS coronavirus (SARS-CoV-2) global pandemic has taken a strong foothold and it
is estimated that it will infect hundreds of millions of people, with millions dying. These estimates
underscore the severity of the COVID-19 disease, caused by SARS-CoV-2, yet there are currently
no effective treatments that can be administered to infected individuals. Our approach centered
around a proprietary structure-based drug discovery engine, which combines rapid screening of
a molecular fragment library in a fragment-based drug discovery approach with high-throughput
X-ray crystallography. We will discover and develop novel small molecule inhibitors of the receptor
binding domain (RBD) of the SARS-CoV-2 viral spike protein S1 subunit (attachment inhibitors),
inhibitors of the viral spike protein S2 subunit (fusion inhibitors), and the Nsp14-Nsp10 complex
(replication mismatch repair inhibitors). Our approach resolves an important step in early drug
discovery, i.e., the generation of reliable, high-quality, target-specific hits that can be advanced to
therapeutics development. Our method provides experimental validation and unprecedented
ability to visualize 3D protein-ligand interactions in a single step, delivering valuable actionable
assets (identification and definition of binding sites and binding pose) for immediate chemistry
and biology follow up in early drug discovery. Our goal is to target conserved amino acid residues
within these proteins to discover and advance molecules that may inhibit the SARS-CoV-2
proteins and also serve as pan-coronavirus inhibitors. Thus we will create broad-spectrum
antiviral therapeutics against multiple coronavirus strains and against the homologous proteins in
SARS and MERS, thereby effectively creating treatments for both current and future coronavirus
outbreaks. We will determine X-ray crystal structures of the SARS-CoV-2 RBD, S2 and Nsp14-
Nsp10 proteins bound to molecular fragments and elaborate these fragment hits into inhibitors
through a combination of computational and medicinal chemistry, high-throughput structural
biology, and biophysical assays.
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