Inhibition of HECT E3 ligases as potential therapy for COVID-19

Abstract

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

SARS-CoV-2 PLpro whole human proteome cleavage prediction and enrichment/depletion analysis

“…[61] Although none of the few ISG15 enzymes are cleaved by either coronavirus protease, NEDD4, which is likely eventually inhibited by free ISG15 released by PLpro's deISGylating activity, [62] is predicted to be cleaved by 3CLpro[1] and has been suggested as a therapeutic target for COVID-19 due to its upregulation in infected cells and probable involvement in egress via non-degradative ubiquitination of viral proteins. [63] The counterintuitive proviral activity of NEDD4 yet potential inhibition directly by 3CLpro and indirectly by PLpro hints that its regulation may be infection time dependent.…”

Syncytia formation during SARS-CoV-2 lung infection: a disastrous unity to eliminate lymphocytes

“…It is imperative to examine whether fluvoxamine affects syncytia formation. It is also worthy to evaluate the whether the combine uses of anti-syncytia drugs with other COVID-19 targets would yield better clinical outcomes [ 14 , 15 ].…”

Update on human genetic susceptibility to COVID-19: susceptibility to virus and response

“…Furthermore, it is clear that precision medicine has the potential to reduce side effects and to reduce hospitalization costs and duration [83]. Studying new therapeutic approaches [84][85][86][87][88], unveiling new molecular mechanisms [88][89][90], understanding the implications of possible susceptibility alleles in the exposed population [91,92], will allow us to broaden our contribution to the fight against the current coronavirus outbreak and against upcoming agents which, inevitably, will show up in the near future [93]. With this goal, we make the commitment to constantly update the tool provided within this paper with new data, in order to have an even more precise, in-depth and proactive overview.…”