Structure-based HIV-1 Integrase Inhibitor Design: a Future Perspective

The pol gene of HIV-1 encodes for three essential enzymes, protease (PR), reverse transcriptase (RT) and integrase (IN). More than 16 drugs, targeting two of these enzymes, PR and RT have been approved by the FDA. At present, there are no clinically useful agents that inhibit the third enzyme, IN. Combination chemotherapy consisting of PR and RT inhibitors has shown remarkable success in the clinic and has benefited many patients. It is thought that a combination of drugs targeting all three enzymes should further incapacitate the virus. Discovery of highly selective PR inhibitors owe their success to the recent development in structure-guided drug design. During the past several years a plethora of structures of HIV-1 PR in complex with an inhibitor have been solved by x-ray crystallography. This incredible wealth of information provided opportunities for the discovery of second and third generation inhibitors. Due to the inherent nature of IN and insufficient structural information, structure-based inhibitor design selective for IN has not kept pace. However, because of recent developments in the field such information could soon become available. In this review, emphasis is placed on inhibitors with identified or proposed drug binding sites on IN.