During the past two decades, great strides have been made in the design of
peptidomimetic drugs for the treatment of
viral infections, despite the stigma of poor
drug-like properties, low oral absorption, and high clearance associated with such compounds. This Account summarizes the progress made toward overcoming such liabilities and highlights the
drug discovery efforts that have focused specifically on human immunodeficiency virus (HIV) and hepatitis C virus (HCV)
protease inhibitors. The arsenal against the incurable disease
AIDS, which is caused by
HIV infection, includes
peptidomimetic compounds that target the virally encoded aspartic
protease enzyme. This
enzyme is essential to the production of mature HIV particles and plays a key role in maintaining infectivity. However, because of the rapid genomic evolution of viruses, an inevitable consequence in the treatment of all
viral infections is the emergence of resistance to the drugs. Therefore, the incomplete suppression of HIV in treatment-experienced
AIDS patients will continue to drive the search for more effective therapeutic agents that exhibit efficacy against the mutants raised by the earlier generation of
protease inhibitors. Currently, a number of substrate-based
peptidomimetic agents that target the virally encoded HCV NS3/4A
protease are in clinical development. Mechanistically, these inhibitors can be generally divided into activated carbonyls that are transition-state mimics or compounds that tap into the feedback mode of
enzyme-product inhibition. In the HCV field, there is justified optimism that a number of these compounds will soon reach commercialization as therapeutic agents for the treatment of HCV
infections. Structural research has guided the successful design of both HIV and HCV
protease inhibitors. X-ray crystallography, NMR, and computational studies have provided valuable insight in to the free-state preorganization of
peptidomimetic ligands and their
enzyme-bound conformation. Researchers have designed a variety of novel bioisosteric replacements of
amino acids and short
peptides that contain all of the required pharmacophore moieties and play a key role in inducing conformational changes to the overall molecule. The knowledge gained from these studies will undoubtedly guide the future design of therapeutic agents and further contribute to the success of this field.