Inhibition of RNA Helicases of ssRNA⁺ Virus Belonging to Flaviviridae, Coronaviridae and Picornaviridae Families

Abstract

Many viral pathogens encode the motor proteins named RNA helicases which display various functions in genome replication. General strategies to design specific and selective drugs targeting helicase for the treatment of viral infections could act via one or more of the following mechanisms: inhibition of the NTPase activity, by interferences with ATP binding and therefore by limiting the energy required for the unwinding and translocation, or by allosteric mechanism and therefore by stabilizing the conformation of the enzyme in low helicase activity state; inhibition of nucleic acids binding to the helicase; inhibition of coupling of ATP hydrolysis to unwinding; inhibition of unwinding by sterically blocking helicase translocation. Recently, by in vitro screening studies, it has been reported that several benzotriazole, imidazole, imidazodiazepine, phenothiazine, quinoline, anthracycline, triphenylmethane, tropolone, pyrrole, acridone, small peptide, and Bananin derivatives are endowed with helicase inhibition of pathogen viruses belonging to Flaviviridae, Coronaviridae, and Picornaviridae families.

Identification and Analysis of Inhibitors Targeting the Hepatitis C Virus NS3 Helicase

“…It should be appreciated that many other assays are available to identify inhibitors of HCV helicase, which have been the subject of other recent reviews (Belon and Frick, 2009a, 2011). There are also other resources available that summarize compounds that have been discovered to inhibit HCV helicase (Belon and Frick, 2009a, 2011; Borowski et al ., 2000; Briguglio et al ., 2011; Lemon et al ., 2010) and compounds that target other helicases (Frick, 2003; Frick and Lam, 2006; Kwong et al ., 2005). …”

Mechanistic insights into Zika virus NS3 helicase inhibition by Epigallocatechin-3-gallate

“…We have chosen NS3 helicase protein of ZIKV, a crucial enzyme in viral replication which unwinds genomic RNA after deriving energy from intrinsic nucleoside triphosphatase (NTPase) activity (18,19). In addition to RNA unwinding activity, flavivirus helicases have also been reported to participate in other vital functions such as ribosome biogenesis, pre-mRNA splicing, RNA export and degradation, RNA maturation as well as translation etc (20). Hence, essential functions of these helicases are making them attractive drug targets.…”

Insights on early mutational events in SARS-CoV-2 virus reveal founder effects across geographical regions

“…One interesting feature of the mutations in this limited number of samples is the evolutionary pressure undergone helicase gene. RNA helicases display various functions in genome replication, and it has been proposed as a therapeutic target to inhibit coronaviruses among other viruses with small molecules (Briguglio et al 2011). Helicase evolution in SARS-CoV-2 could be rapidly occurring, making it unfeasible to drug this protein in the future.…”