Anti-HIV-1 integrase drugs: How far from the shelf?

Chemotherapy of HIV-I infection/AIDS currently employs inhibitors of two pr oducts of the viral pol gene, the reverse transcriptase acid protease enzym es. However, a third product of the pol gene is essential for retroviral mu ltiplication, the integrase. As no cellular homologue of HIV integrase has been described, potential inhibitors could be relatively nontoxic. Developm ent of HIV-1 integrase inhibitors could have favorable implication for comb ination therapy, including potential synergy with currently available inhib itors, as well as prevention of the chronic carrier state and the emergence of resistant mutants. Although several classes of putative integrase inhib itors that been described, still no clinically useful anti-integration drug s are available. It is the structural and functional complexity of the inte gration process together with the limitations of the available in vitro ass ays that has made it problematic to develop inhibitors of the HIV integrase . In this review we summarize current knowledge concerning the biology of t his enzyme and of the integration process, and discuss major classes repres entatives of integrase inhibitors considering the obstacles to the developm ent of true anti-integrase drugs.