Allosteric Inhibitor Development Targeting HIV‐1 Integrase

HIV‐1 integrase (IN) is one of three essential enzymes for viral replication, and is a focus of ardent antiretroviral drug discovery and development efforts. Diligent research has led to the development of the strand‐transfer‐specific chemical class of IN inhibitors, with two compounds from this group, raltegravir and elvitegravir, advancing the farthest in the US Food and Drug Administration (FDA) approval process for any IN inhibitor discovered thus far. Raltegravir, developed by Merck & Co., has been approved by the FDA for HIV‐1 therapy, whereas elvitegravir, developed by Gilead Sciences and Japan Tobacco, has reached phase III clinical trials. Although this is an undoubted success for the HIV‐1 IN drug discovery field, the emergence of HIV‐1 IN strand‐transfer‐specific drug‐resistant viral strains upon clinical use of these compounds is expected. Furthermore, the problem of strand‐transfer‐specific IN drug resistance will be exacerbated by the development of cross‐resistant viral strains due to an overlapping binding orientation at the IN active site and an equivalent inhibitory mechanism for the two compounds. This inevitability will result in no available IN‐targeted therapeutic options for HIV‐1 treatment‐experienced patients. The development of allosterically targeted IN inhibitors presents an extremely advantageous approach for the discovery of compounds effective against IN strand‐transfer drug‐resistant viral strains, and would likely show synergy with all available FDA‐approved antiretroviral HIV‐1 therapeutics, including the IN strand‐transfer‐specific compounds. Herein we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non‐active‐site regions to inhibit IN function.