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. 1. Introduction To convert a closed double-stranded DNA or RNA helix into two open single strands, so that other protein machinery can manipulate the polynucleotides, the cells require helicases. They are motor proteins that use energy derived from ATP hydrolysis [1–4]. Several DNA and RNA helicases have been isolated from all kingdoms of life, from virus to man [5–8]. Detailed structural information, biological mechanisms, and clear outlook on inhibitors of therapeutic relevance as antiviral agents are recently provided by Xi et al. [9], Kwong et al. [10], and overall Frick et al. [11, 12]. Several ssRNA+ (positive sense single-stranded RNA) helicases have been studied in detail including those from Dengue fever virus (DFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV). More in general, a recent article on anti-Flaviviridae chemotherapy has been published by Ghosh and Basu [13], who expand the original information regarding the role of helicases in Flaviviridae previously reported by Borowski [14]. This enzyme is a promising target to develop new therapies and preventative agents, since ssRNA+ viruses belonging to families like Flaviviridae, Coronaviridae, and Picornaviridae cause clinically significant diseases both in humans and animals, determining life lost, economical loss, and higher productivity costs. Examples are the bovine viral diarrhea virus (BVDV), a serious welfare problem that significantly damages the farm business, and the
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