115 The Design and Development of HIV-1 Intergrase Inhibitors: Past, Present and Future Daria Hazuda Merck Res Labs, West Point, PA, USA

Integrase remains a promising target for the development of novel antiretroviral agents to treat HIV-1 infection.  The viability of integrase as a therapeutic target has been validated in vitro as well as in experimental animal model systems of retroviral infection and clinical proof of concept has now been achieved in HIV-1 infected patients. Understanding the basic mechanism of action of prototype inhibitors in vitro has been instrumental in the evolution of compounds which are suitable for clinical development. In the absence of relevant structural information, we have also used the insights gained from studying the cross resistance patterns of structurally diverse inhibitors to facilitate this process.   Although the first wave of integrase inhibitors are in the earliest stages of clinical study, data from these in vitro studies has suggested unexpected opportunities for the design of “second generation” compounds and an understanding of the potential complexities of the effects of resistance mutations on the function of integrase in HIV-1 replication that may prove pertinent to the clinical development of this novel class of antiretroviral agents This presentation will review the role of integrase in HIV-1 infection, the mechanism of integrase inhibitors and key features shared by recently disclosed compounds from our labs and other groups as well as summarize the results of resistance analyses with an emphasis on the potential implications for drug development.