Targeted protein S-nitrosylation of ACE2 as potential treatment to prevent spread of SARS-CoV-2 infection.

Abstract

Prevention of infection and propagation of SARS-CoV-2 is of high priority in the COVID-19 pandemic. Here, we describe S-nitrosylation of multiple proteins involved in SARS-CoV-2 infection, including angiotensin converting enzyme 2 (ACE2), the receptor for viral entry. This reaction prevents binding of ACE2 to the SARS-CoV-2 Spike protein, thereby inhibiting viral entry, infectivity, and cytotoxicity. Aminoadamantane compounds also inhibit coronavirus ion channels formed by envelope (E) protein. Accordingly, we developed dual-mechanism aminoadamantane nitrate compounds that inhibit viral entry and thus spread of infection by S-nitrosylating ACE2 via targeted delivery of the drug after E-protein channel blockade. These non-toxic compounds are active in vitro and in vivo in the Syrian hamster COVID-19 model, and thus provide a novel avenue for therapy.

• Authors: Chang-Ki Oh, Tomohiro Nakamura, Nathan Beutler, Xu Zhang, Juan Piña-Crespo, Maria Talantova, Swagata Ghatak, Dorit Trudler, Lauren N Carnevale, Scott R McKercher, Malina A Bakowski, Jolene K Diedrich, Amanda J Roberts, Ashley K Woods, Victor Chi, Anil K Gupta, Mia A Rosenfeld, Fiona L Kearns, Lorenzo Casalino, Namir Shaabani, Hejun Liu, Ian A Wilson, Rommie E Amaro, Dennis R Burton, John R Yates, Cyrus Becker, Thomas F Rogers, Arnab K Chatterjee, Stuart A Lipton
• Journal: bioRxiv : the preprint server for biology (bioRxiv) (Apr 05 2022) United States
• PMID: 35411336 (Publication Type: Preprint)