Targeted protein S-nitrosylation of ACE2 as potential treatment to prevent spread of SARS-CoV-2 infection

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. ### Competing Interest Statement The authors declare that S.A.L. is an inventor on patents for the use of memantine and various aminoadamantane nitrate compounds for neurodegenerative and neurodevelopmental disorders. He is also an inventor on composition of matter patents and use patents for aminoadamantane nitrate compounds in treating COVID-19 and other viral diseases. Per Harvard University guidelines, S.A.L. participates in a royalty-sharing agreement with his former institution Boston Childrens Hospital/Harvard Medical School, which licensed the drug memantine (Namenda) to Forest Laboratories, Inc./Actavis/Allergan/AbbVie for use in dementia. The aminoadamantane nitrate compounds have been licensed to EuMentis Therapeutics, Inc. (Newton, Massachusetts). C.B. is a chemist employed at EuMentis Therapeutics. The other authors declare no financial conflicts of interest relevant to this publication.