Integrase Inhibitors: Redefining HIV-1 Treatment and Future Challenges.

The discovery and development of HIV-1 integrase strand transfer inhibitors (INSTIs) represent one of the remarkable success stories in antiviral drug discovery, transforming fundamental insights of retroviral enzymology into highly effective first-line therapies for HIV-1/AIDS patients. Currently there are five INSTIs approved for clinical use. Among these, second generation drugs Dolutegravir, Bictegravir and Cabotegravir offer excellent virologic suppression, favorable tolerability and a high genetic barrier to resistance. The long-acting formulation of the most recent INSTI Cabotegravir has also been approved for pre-exposure prophylaxis in high-risk populations. Apart from inhibiting the active site of integrase, a new class of allosteric integrase inhibitors (ALLINIs), which target integrase multimerization affecting multiple steps in viral life cycle, are in the advanced phases of clinical trials. The mechanisms of HIV-1 integration, development of integrase inhibitors, structural biology breakthroughs that guided inhibitor optimization and clinical use of INSTIs, their successes and challenges for HIV/1AIDS management are reviewed here.