D. J. Kempf* and H. L. Sham Pages 225 - 246 ( 22 )
The protease encoded by the human immunodeficiency virus (HIV protease) mediates the maturation of newly formed HIV particles through proteolytic processing of the gag and gag-pol gene products. Because of its essential role in the HIV replication cycle, this enzyme represents a logical target for the treatment of HIV infection. The intimate knowledge of the function and three-dimensional structure of HIV protease has prompted numerous approaches to the rational design of inhibitors. Despite rapid advances in the design of potent and specific inhibitors, the identification of clinically viable agents has proven challenging, the greatest obstacle being the problem of poor pharmacodynamic properties. Nonetheless, clinical trials of agents with substantially improved pharmacological properties Ii.ave demonstrated that protease inhibitors can produce a dramatic antiviral effect in vivo. In this chapter, recent approaches to HIV protease inhibitor design, with a particular focus on advances in the preclinical pharmacokinetic properties, are reviewed.