SURFing SARS-CoV-2 inhibition

Abstract

Yang et al. present the fluorogenic reversible reporter SURF to monitor real-time interactions between the SARS-CoV-2 spike protein and ACE2, and identify compounds that block such interaction.

To start infection, SARS-CoV-2 uses its spike protein to interact with the host receptor angiotensin-converting enzyme 2 (ACE2). Currently, small-molecule drugs that stop SARS-CoV-2 infection are urgently needed. In this new study, Yang et al. present an improved fluorogenic reversible reporter named SURF (split UnaG-based reversible and fluorogenic protein–protein interaction reporter) to visualize real-time interactions between the spike protein and ACE2 in living cells and thus identify compounds that block such interaction. First, the authors engineered the reporter to become fluorescent when spike and ACE2 interact. Next, they adapted SURF and made it suitable for high-throughput screening of approved drugs and natural compound libraries to select the best candidates inhibiting spike–ACE2 interaction. Gamabufotalin, anisomycin and bruceine A were the top compounds blocking receptor binding of SARS-CoV-2, including Delta and Omicron variants, in vitro. In particular, bruceine A and gamabufotalin showed effective antiviral activity against SARS-CoV-2 infection in primary human cells and in mice, and they were effective when administered together as prophylactic treatment. In sum, the SURF reporter is a valuable resource to identify inhibitors of SARS-CoV-2 infection.