학술논문
Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
Document Type
Original Paper
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, III, John R.; Becker, Cyrus; Rogers, Thomas F.; Chatterjee, Arnab K.; Lipton, Stuart A.
Source
Nature Chemical Biology. 19(3):275-283
Subject
Language
English
ISSN
1552-4450
1552-4469
1552-4469
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.
Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.
Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.