Inhibition of the NS2B-NS3 protease - Towards a causative therapy for dengue virus diseases

Abstract

The high impact of diseases caused by dengue viruses on global health is now reflected in an increased interest in the identification of drug targets and the rationale-based development of antiviral inhibitors which are suitable for a causative treatment of severe forms of dengue virus infections - dengue haemorrhagic fever and dengue shock syndrome. A promising target for the design of specific inhibitors is the dengue virus NS3 serine protease which - in the complex with the small activator protein NS2B - catalyses processing of the viral polyprotein at a number of sites in the nonstructural region. The NS3 protease is an indispensable component of the viral replication machinery and inhibition of this protein offers the prospect of eventually preventing dengue viruses from replication and maturation. After nearly a decade of mainly genetic analysis of flaviviral replication, recent studies have contributed substantial biochemical information on polyprotein processing including the 3-dimensional structure of the dengue virus NS3 protease domain, the mechanism of co-factor-dependent activation and sensitive in vitro assays which are needed for studies on substrate specificity and the development of high-throughput assays for inhibitor screening. This review discusses recent biochemical findings which are relevant to the design of potential inhibitors directed against the dengue virus NS3 protease.