학술논문
Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
Document Type
article
Author
Oh, Chang-ki; Nakamura, Tomohiro; Beutler, Nathan; Zhang, Xu; Piña-Crespo, Juan; Talantova, Maria; Ghatak, Swagata; Trudler, Dorit; Carnevale, Lauren N; McKercher, Scott R; Bakowski, Malina A; Diedrich, Jolene K; Roberts, Amanda J; Woods, Ashley K; Chi, Victor; Gupta, Anil K; Rosenfeld, Mia A; Kearns, Fiona L; Casalino, Lorenzo; Shaabani, Namir; Liu, Hejun; Wilson, Ian A; Amaro, Rommie E; Burton, Dennis R; Yates, John R; Becker, Cyrus; Rogers, Thomas F; Chatterjee, Arnab K; Lipton, Stuart A
Source
Nature Chemical Biology. 19(3)
Subject
Language
Abstract
Prevention of infection and propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a high priority in the Coronavirus Disease 2019 (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, the 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 to pursue therapy.