Pilar Najarro, Neil Mathews and Stuart Cockerill
from: Hepatitis C: Antiviral Drug Discovery and Development (Edited by: Seng-Lai Tan and Yupeng He). Caister Academic Press, U.K. (2011)
The HCV NS5A protein plays critical roles in the life cycle of the virus and has been associated with a multitude of host-pathogen events associated with NS5A. As part of the replication complex, it is essential for RNA replication. In addition, its propensity to engage in many protein-protein interactions enables this protein to facilitate the assembly of viral particles and to counteract the host immune response. However, the inherent intractability of NS5A as a drug target has caused it to be of low priority in the "rational drug hunter" portfolio of anti-viral arsenals. A lack of enzymatic or receptor functionality, a paucity of structural data and limited evidence for an ability to directly bind small molecules have all conspired against it. The development of HCV subgenomic replicon technology provided an opportunity to identify inhibitors of HCV with mechanisms distinct from the established targets, i.e. polymerase and protease. Whole cell screening using the replicon technology and subsequent generation of replicon mutants has pointed to NS5A as being the likely target of a number of hit compounds A number of companies have now developed, through lead optimisation, highly selective and potent inhibitors of NS5A. Recently these efforts have culminated in a clinical proof of concept and established NS5A as a valid target for development of small-molecule therapies read more ...