Targeted protein S-nitrosylation of ACE2 as potential treatment to prevent spread of SARS-CoV-2 infection.
Chang-Ki OhTomohiro NakamuraNathan BeutlerXu ZhangJuan Piña-CrespoMaria TalantovaSwagata GhatakDorit TrudlerLauren N CarnevaleScott R McKercherMalina A BakowskiJolene K DiedrichAmanda J RobertsAshley K WoodsVictor ChiAnil K GuptaMia A RosenfeldFiona L KearnsLorenzo CasalinoNamir ShaabaniHejun LiuIan A WilsonRommie Elizabeth AmaroDennis R BurtonJohn R YatesCyrus BeckerThomas F RogersArnab K ChatterjeeStuart A LiptonPublished in: bioRxiv : the preprint server for biology (2022)
Prevention of infection and propagation of SARS-CoV-2 is of high priority in the 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 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 for therapy.