The target landscape of N4-hydroxycytidine based on its chemical neighborhood

Abstract

N4-hydroxycytidine (NHC) has been recently reported to have promising antiviral activity against SARS-CoV-2. To join worldwide efforts in identifying potential drug targets against this pandemic, the target landscape of NHC was defined by extracting all known targets of its chemical neighborhood, including drugs, analogues, and metabolites, and by performing target predictions from two independent platforms, following the recent Public Health Assessment via Structural Evaluation (PHASE) protocol. The analysis provides a list of over 30 protein targets that could be useful in future design activities of new COVID-19 antivirals. The relevance for existing drugs within the same chemical space, such as remdesivir, is also discussed.

COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2

“…It is important to note that this agent showed extensive potency against RDV resistant CoV mutations (14). The small ring size of NHC blocks virus cell entry (50). Furthermore, its resemblance with potent antivirals, such as cytidine, supports its antiviral effect (50).…”

“…The small ring size of NHC blocks virus cell entry (50). Furthermore, its resemblance with potent antivirals, such as cytidine, supports its antiviral effect (50). Given its pharmacologic profile, its privilege of oral administration and its antiviral activity, this active substance could be a treatment against COVID-19.…”

A Workflow of Integrated Resources to Catalyze Network Pharmacology Driven COVID-19 Research

“…The DTIs were originally extracted from scientific literature, drug labels, and other data sources such as, ChEMBL, 4 IUPHAR Guide2Pharmacology, 91 WOM-BAT-PK, 92 DrugBank, 93 To further enrich the network, we included both known and predicted DTIs for drugs and human endogenous metabolites found in the vicinities of the chemical space defined by three small molecules being investigated at the time for their antiviral activity against SARS-CoV-2 assays, namely, N4-hydroxycytidine (NHC), 95 hydroxychloroquine (HCQ), 70 and camostat (CAM). 96 A set of 25 compounds was compiled around NHC 97 and 5 around the chemical neighborhood of HCQ, and camostat. Processing those 31 small molecules against the CLARITY platform 98 returned a total of 86 DTIs, known (from public sources 5 ) or predicted 99 to have activity against 46 unique protein targets (resource D).…”

A Workflow of Integrated Resources to Catalyze Network Pharmacology Driven COVID-19 Research

“…To further enrich the network, we included both known and predicted DTIs for drugs and human endogenous metabolites found in the vicinities of the chemical space defined by three small molecules being investigated at the time for their antiviral activity against SARS-CoV-2 assays, namely, N4-hydroxycytidine (NHC) [63], hydroxychloroquine (HCQ) [64], [65] and camostat (CAM) [66]. A set of 25 compounds was compiled around NHC [67], 5 around the chemical neighborhood of HCQ, and camostat. Processing those 31 small molecules against the CLARITY platform [68] returned a total of 86 DTIs, known (from public sources [5]) and/or predicted [69] to have activity against 46 unique protein targets (data track “F”).…”