Development of HIV-1 Allosteric Reverse Transcriptase (RT) Inhibitors

Abstract

Forty years after the initial outbreak, HIV/AIDS remains one of the major global public health issues. The development of the Highly Active Antiretroviral Therapy (HAART) has made it possible to delay the progress of the disease hence prolonging survival, however, as the virus continues to evolve rapidly, issues are rising surrounding the resistance to the available drugs as well as associated toxicities. Therefore, the search for new drugs is an ongoing process. A key viral enzyme in HIV is Reverse Transcriptase (RT), which interacts with various viral proteins and cellular factors at different stages in reverse transcription. Previous studies have reported a protein-protein interaction (PPI) involving RT and the cellular eukaryotic translation elongation factor 1A (eEF1A), which could serve as potential new target for drug discovery. The eEF1A protein is a dominant cellular factor that plays a pivotal role in protein synthesis to ensure successful replication of a number of RNA viruses. In HIV, eEF1A is required in the late stages of reverse transcription and impairing binding of RT to eEF1A results in significant reduction in reverse transcription efficiency, ultimately leading to defective viral replication. The region of the RT that is required for interaction with eEF1A has recently been identified which presents as a valuable target for novel drug design. The development of drugs targeting this PPI in HIV could be the new treatment paradigm as there is potential of both an effective prophylactic agent and maintenance treatment. This work is based on targeting the RT-eEF1A interaction by identifying new small molecule leads through an in-silico screening programme, followed by the synthesis and testing of those leads. Several leads and associated analogues have been shown to inhibit the interaction between RT and eEF1A however, future work must be undertaken to quantify the level of inhibition.