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Publisher Summary Hepatitis C virus (HCV) is a blood-borne pathogen belonging to the Flaviviridae family of viruses, which also includes the West Nile, Yellow Fever, and Dengue viruses. Most small molecule inhibitor approaches to HCV have been focused on inhibition of essential viral targets, particularly the NS3-4A protease and the NS5B RNA-dependent RNA polymerase although other targets are being pursued. A variety of nucleoside competitive inhibitors of HCV NS5B, the RdRp encoded at the 3´-terminal portion of the HCV genome and required for viral replication, have also been thoroughly studied and advanced to clinical trials. By analogy to AIDS, where HIV protease plays a crucial role in processing mature virions, HCV uses the NS3-4A (aka NS3) protease in a similar manner making it a very attractive inhibition target. The key difference between the two proteases is that the HIV protease active site forms a well-defined active site while the NS3 protease has a shallow cleft with fewer opportunities to bind to small molecules. As a result, NS3 inhibitors have been generally more complex, more peptide-like and larger than those for HIV.

The most important unresolved issues impacting the design of future TACE inhibitors are the frequent discrepancies between activity measured in cell-free TACE assays and cellular assays of LPS-stimulated TNF-α, and the desired TACE/MMP selectivity profile to provide adequate efficacy and safety. Many factors, most natably cell permeability and protein binding have been considered in obtaining highly active compounds in cells. The possibility that differences in the membrane bound enzyme and cell-free enzyme alter the configuration of the S1′ and S3′ enzyme subsites has also been addressed (61). The assessment of preferred TACE/MMP selectivity profiles awaits further clinical testing of TACE inhibitors against various pathologies. The development of new enzyme assays, including a continuous fluorometric TACE assay and a high-throughput screen based on a phage-displayed TACE catalytic domain should also aid in the rapid identification of new inhibitors (62, 63). A recent study of the binding process for hydroxamate and carboxylate TACE ligands may also be valuable for inhibitor design (64).