In search of second-generation HIV integrase inhibitors: targeting integration beyond strand transfer.

Highly active antiretroviral therapy combines antiviral drugs targeting different steps in the HIV replication cycle in order to reduce viral loads in patients to undetectable levels. Since HIV readily develops resistance and can therefore escape the action of existing drugs, novel drugs with novel mechanisms of action must be developed. The integration of the viral genome into the human genome is an essential and critical replication step that is catalyzed by the viral integrase with the help of cellular cofactors. Although HIV-1 integrase has been studied for more than two decades, the first integrase inhibitor, raltegravir, was only recently approved for clinical use. A second compound, elvitegravir, is currently in advanced clinical trials. Both drugs interfere with the strand-transfer reaction of integrase. Due to the complexity and multistep nature of the integration reaction, several other functions of integrase can be exploited for drug discovery. In this review, we will describe these alternative strategies to inhibit integration. They have recently attracted considerable interest for the development of second-generation integrase inhibitors.