Helicases as antiviral drug targets

Abstract

Helicases catalytically unwind duplex DNA or RNA using energy derived from the hydrolysis of nucleoside triphosphates and are attractive drug targets because they are required for viral replication. This review discusses methods for helicase identification, classification and analysis, and presents an overview of helicases that are necessary for the replication of human pathogenic viruses. Newly developed methods to analyze helicases, coupled with recently determined atomic structures, have led to a better understanding of their mechanisms of action. The majority of this research has concentrated on enzymes encoded by the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Helicase inhibitors that target the HSV helicase-primase complex comprised of the UL5, UL8 and UL52 proteins have recently been shown to effectively control HSV infection in animal models. In addition, several groups have reported structures of the HCV NS3 helicase at atomic resolutions, and mechanistic studies have uncovered characteristics that distinguish the HCV helicase from related cellular proteins. These new developments should eventually lead to new antiviral medications.

Fig. 1

Role of helicase in viral replication. Helicases unwind duplex DNA or RNA intermediates formed during viral replication in a reaction driven by energy derived from the hydrolysis of nucleoside triphosphates.

Fig. 2

Structure of the hepatitis C virus helicase DNA complex. Schematic representation of NS3 helicase bound to a polyU ssDNA (arrow) with a sulfate ion (space-fill) bound in the putative ATP binding site. Conserved motifs are shown as colored ball/sticks. Coordinates are from Protein Data Bank entry 1A1V.

Fig. 3

Inhibitors of herpes simplex virus replication. Structures of the nucleoside analogue drug acyclovir, the 2-amino thiazole derivative T-157602 identified by Tularik Inc., the Boehringer Ingelheim compound BILS-179 BS and the inhibitor BAY-57-1293 reported by Bayer.