Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication

Abstract

Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound 1c strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3′-to-5′ exoribonuclease (ExoN). While 1c inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound 1c in the catalytic pocket of the ExoN domain of nsp14. Finally, 1c inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that 1c might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases.

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“…Dynasore also regulates cellular cholesterol homeostasis and induces actin remodeling. More recently, it was shown that dynasore and its derivatives are strong inhibitors of viral ribonucleases necessary for the processing of RNA molecules [33,34]. Dynamin proteins play crucial roles in the life cycle of T. gondii parasites [35][36][37].…”

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“…The exoribonuclease domain of Nsp14 interacts with its cofactor Nsp10 to correct viral RNA mispairing by removing misincorporated nucleotides or nucleotide analogues from the 3′-end of the nascent RNA strand, a proofreading mechanism that is essential for the maintenance of the replicative fidelity of the coronavirus genome and is a candidate for antiviral drug targets for antiviral drugs [ 66 ]. Based on molecular docking technology, a number of Nsp14 inhibitors targeting the active site of exoribonuclease have been identified [ 67 ], such as nitrocatechol [ 68 ], SGC0946, and SGC8158 [ 69 ]. However, there is an off-target effect due to the structural similarity between Nsp14 and human DEDD exonuclease.…”