1. Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
- 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, and Lipton, Stuart A
- Subjects
Vaccine Related ,Emerging Infectious Diseases ,Prevention ,Pneumonia & Influenza ,Biodefense ,Pneumonia ,Infectious Diseases ,Lung ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Infection ,Good Health and Well Being ,Humans ,COVID-19 ,SARS-CoV-2 ,Angiotensin-Converting Enzyme 2 ,Protein Binding ,Peptidyl-Dipeptidase A ,Medicinal and Biomolecular Chemistry ,Biochemistry and Cell Biology ,Biochemistry & Molecular Biology - 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.
- Published
- 2023