Targeting novel sites on reverse transcriptase for HIV treatment and prevention

HIV remains a major public health threat. The World Health Organisation (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommend global scale-up of antiretroviral drugs for HIV treatment and prevention but drug resistance and toxicity could lead to exhaustion of drug options, particularly in resource-poor settings, with little in the way of new drug classes in the pipeline. HIV reverse transcriptase (RT) is an essential viral enzyme and a validated drug target. There are only two drug classes used for HIV treatment and prevention that target HIV RT and they bind only two distinct sites on the RT enzyme. Resistance to a drug in one class usually confers cross-resistance to other drugs in the same class limiting their use. Through fragment based drug screening, a relatively new paradigm in drug discovery, our team has discovered new chemical drug building blocks that have distinct mechanisms of action and bind to novel allosteric sites on the RT.

Our overall aim is to characterise these new drug scaffolds and their novel binding sites on HIV RT to advance fundamental understanding of RT structure and function and to underpin the discovery of a new HIV drug class. This new drug class is aimed to have a distinct mechanism of action and resistance profile to drugs currently used for HIV treatment and prevention.