tetano
Editor, Senior Moderator
Nat Chem Biol
. 2022 Sep 29.
doi: 10.1038/s41589-022-01149-6. Online ahead of print.
Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
Chang-Ki Oh[SUP] 1 [/SUP], Tomohiro Nakamura[SUP] 1 [/SUP], Nathan Beutler[SUP] 2 [/SUP], Xu Zhang[SUP] 1 [/SUP], Juan Piña-Crespo[SUP] 1 [/SUP], Maria Talantova[SUP] 1 [/SUP], Swagata Ghatak[SUP] 1 [/SUP], Dorit Trudler[SUP] 1 [/SUP], Lauren N Carnevale[SUP] 1 [/SUP], Scott R McKercher[SUP] 1 [/SUP], Malina A Bakowski[SUP] 3 [/SUP], Jolene K Diedrich[SUP] 1 [/SUP], Amanda J Roberts[SUP] 4 [/SUP], Ashley K Woods[SUP] 3 [/SUP], Victor Chi[SUP] 3 [/SUP], Anil K Gupta[SUP] 3 [/SUP], Mia A Rosenfeld[SUP] 5 [/SUP], Fiona L Kearns[SUP] 5 [/SUP], Lorenzo Casalino[SUP] 5 [/SUP], Namir Shaabani[SUP] 2 [/SUP], Hejun Liu[SUP] 6 [/SUP], Ian A Wilson[SUP] 6 [/SUP], Rommie E Amaro[SUP] 5 [/SUP], Dennis R Burton[SUP] 2 [/SUP], John R Yates 3rd[SUP] 1 [/SUP], Cyrus Becker[SUP] 7 [/SUP], Thomas F Rogers[SUP] 2 8 [/SUP], Arnab K Chatterjee[SUP] 3 [/SUP], Stuart A Lipton[SUP] 9 10 [/SUP]
Affiliations
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.
. 2022 Sep 29.
doi: 10.1038/s41589-022-01149-6. Online ahead of print.
Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
Chang-Ki Oh[SUP] 1 [/SUP], Tomohiro Nakamura[SUP] 1 [/SUP], Nathan Beutler[SUP] 2 [/SUP], Xu Zhang[SUP] 1 [/SUP], Juan Piña-Crespo[SUP] 1 [/SUP], Maria Talantova[SUP] 1 [/SUP], Swagata Ghatak[SUP] 1 [/SUP], Dorit Trudler[SUP] 1 [/SUP], Lauren N Carnevale[SUP] 1 [/SUP], Scott R McKercher[SUP] 1 [/SUP], Malina A Bakowski[SUP] 3 [/SUP], Jolene K Diedrich[SUP] 1 [/SUP], Amanda J Roberts[SUP] 4 [/SUP], Ashley K Woods[SUP] 3 [/SUP], Victor Chi[SUP] 3 [/SUP], Anil K Gupta[SUP] 3 [/SUP], Mia A Rosenfeld[SUP] 5 [/SUP], Fiona L Kearns[SUP] 5 [/SUP], Lorenzo Casalino[SUP] 5 [/SUP], Namir Shaabani[SUP] 2 [/SUP], Hejun Liu[SUP] 6 [/SUP], Ian A Wilson[SUP] 6 [/SUP], Rommie E Amaro[SUP] 5 [/SUP], Dennis R Burton[SUP] 2 [/SUP], John R Yates 3rd[SUP] 1 [/SUP], Cyrus Becker[SUP] 7 [/SUP], Thomas F Rogers[SUP] 2 8 [/SUP], Arnab K Chatterjee[SUP] 3 [/SUP], Stuart A Lipton[SUP] 9 10 [/SUP]
Affiliations
- PMID: 36175661
- DOI: 10.1038/s41589-022-01149-6
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.