New approaches for inhibiting HIV integrase: a journey beyond the active site

Integrase (IN) inhibitors have proven to be highly beneficial in the treatment of HIV infection. The recently approved inhibitor, raltegravir, the phase III clinical trials compound elvitegravir, and all other agents reported to be in clinical trials bind to the active site of IN and share the same mechanism of action. There is a high probability for the development of cross resistance among these compounds. Therefore, drugs targeting alternative mechanisms and binding sites on IN are desired. Two potential sites for inhibiting the enzyme have been disclosed recently. The first site is located in the catalytic core domain and is used by the enzyme to bind the host protein lens epithelium-derived growth factor. The second site was identified by the selective covalent trapping of pyridoxal phosphate to the C-terminal domain of the enzyme. The targeting of these sites as a potential novel approach for inhibiting HIV IN is reviewed.