UCSF team develops trivalent binder of SARS-CoV-2 spike for COVID-19

DISEASE CATEGORY: Infectious disease

INDICATION: Coronavirus

A UCSF team led by Sunesis Pharmaceuticals Inc. (NASDAQ:SNSS) founder Jim Wells has developed a trivalent immunoglobulin variable heavy domain-based inhibitor of the ACE2-SARS-CoV-2 S interaction that could treat COVID-19 infection. Screening of a synthetic variable heavy chain phage library to identify compounds capable of binding multiple epitopes on SARS-CoV-2 S, including those at the ACE2 binding interface, yielded three leads that bound SARS-CoV-2 S with K_d values of 23-113 nM. The team then assembled these leads into Fc fusions of linked dimers and linked trimers, and performed in vitro and cell-based assays that identified a trivalent variable heavy domain construct as the most potent inhibitor. The construct bound SARS-CoV-2 S with an EC₅₀ of 0.135 nM and blocked viral entry into monkey kidney epithelial cells with an IC₅₀ of 3.98 nM.

Other therapies targeting the ACE2-SARS-CoV-2 S interaction in preclinical testing for COVID-19 include: a camelid neutralizing single-domain antibody from Abcore Inc.; a neutralizing protein from Avacta Group plc (LSE:AVCT); and a synthetic neutralizing antibody from BioDuro LLC.

TARGET/MARKER/PATHWAY: Angiotensin-converting enzyme 2 (ACE2); SARS-CoV-2 spike protein (SARS-CoV-2 S)

EXPERIMENTAL SYSTEM: In vitro; cell culture

LICENSING STATUS: Patent and licensing status unavailable

PUBLICATION DETAILS: Bracken, C. et al. Nat. Chem. Biol.; published online Oct. 20, 2020

doi:10.1038/s41589-020-00679-1

CONTACT: James A. Wells, University of California San Francisco, San Francisco, Calif.

email: jim.wells@ucsf.edu