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Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection.
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.
  • Oh CK; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Nakamura T; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Beutler N; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA.
  • Zhang X; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Piña-Crespo J; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Talantova M; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Ghatak S; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Trudler D; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Carnevale LN; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • McKercher SR; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Bakowski MA; Calibr, a division of the Scripps Research Institute, La Jolla, CA, USA.
  • Diedrich JK; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Roberts AJ; Animal Models Core, Scripps Research Institute, La Jolla, CA, USA.
  • Woods AK; Calibr, a division of the Scripps Research Institute, La Jolla, CA, USA.
  • Chi V; Calibr, a division of the Scripps Research Institute, La Jolla, CA, USA.
  • Gupta AK; Calibr, a division of the Scripps Research Institute, La Jolla, CA, USA.
  • Rosenfeld MA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • Kearns FL; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • Casalino L; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • Shaabani N; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA.
  • Liu H; Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA, USA.
  • Wilson IA; Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA, USA.
  • Amaro RE; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • Burton DR; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA.
  • Yates JR; Departments of Molecular Medicine and Neuroscience, Neurodegeneration New Medicines Center, La Jolla, CA, USA.
  • Becker C; EuMentis Therapeutics, Inc., Newton, MA, USA.
  • Rogers TF; Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, CA, USA.
  • Chatterjee AK; Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Lipton SA; Calibr, a division of the Scripps Research Institute, La Jolla, CA, USA.
Nat Chem Biol ; 2022 Sep 29.
Article in English | MEDLINE | ID: covidwho-2274727
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.
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Full text: Available Collection: International databases Database: MEDLINE Language: English Journal subject: Biology / Chemistry Year: 2022 Document Type: Article Affiliation country: S41589-022-01149-6

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Full text: Available Collection: International databases Database: MEDLINE Language: English Journal subject: Biology / Chemistry Year: 2022 Document Type: Article Affiliation country: S41589-022-01149-6