MI2025 – Wei Shen Ho

Title:
Broadly Neutralizing ACE2 Decoy as a Universal Coronavirus Therapeutic

Abstract:
Many coronaviruses, including members of the alphacoronavirus and betacoronavirus genera, utilize the host angiotensin converting enzyme 2 (ACE2) as the entry receptor for viral infection. Due to the structural similarities between many animal ACE2 with the human homolog, there is potential for zoonotic spillover events. As such, prophylactic or therapeutic treatment options against ACE2-utilizing coronaviruses are required. To address this urgent need, ACE2 decoy receptors were generated and optimized to broadly neutralize both alpha- and betacoronaviruses that exploit the ACE2 pathway for viral entry and infection. Through in silico methods to identify key interaction residues and mutations for favorable binding energetics, a library of ACE2 decoys was generated and synthesized for testing. Our results revealed that the key ACE2 interaction residues differed across betacoronaviruses, as well as between beta- and alphacoronaviruses. The hits that were identified demonstrated breadth in binding to all tested SARS-CoV-2 variants, as well as other human and animal sarbecovirus, merbecovirus, and setracovirus subgenera. Notably, our hits showed at least 7-fold improvements in binding KD and neutralization IC50 against recent variants of SARS-CoV-2, as well as up to 100-fold improvements against animal sarbecoviruses. Overall, the improved ACE2 decoy molecules offer a promising avenue for broad-spectrum coronavirus neutralization as well as provide valuable insights into the ACE2-virus interaction dynamics. Our findings also highlight the adaptability and efficacy of combining computational and high-throughput screening approaches to identify future-proof therapeutics in response to emerging and diverse viral threats.

Biography:
Wei Shen obtained his B.Sc in Chemistry and Ph.D. in Pharmacy and Pharmaceutical Sciences from the National University of Singapore, where he combined medicinal chemistry and chemical biology techniques to discover novel antivirals against the coronavirus nsp14/10 complex. Wei Shen is currently a scientist at the A*STAR Infectious Diseases Labs (A*STAR IDL), where he works on the characterization of functional antibodies against infectious pathogens, the structure-function relationship of host receptors in coronavirus infections, and antibody-drug conjugates against infectious pathogens.