Thursday, April 3, 2025
4/3/2025
Structural basis for activity of and resistance to HIV integrase inhibitors - ABSTRACT The Human Immunodeficiency Virus Type 1 (HIV-1, hereafter referred to as HIV) currently infects ~40 million people worldwide, and the number of infected individuals continues to rise. In the absence of a cure, antiretroviral therapy represents the primary treatment option, because it slows disease progression and reduces new infections. Integrase (IN) Strand Transfer Inhibitors (INSTIs) are a class of antiretroviral therapeutics that block integration of viral DNA into host chromosomes, a process that is mediated by the viral IN enzyme, which assembles into oligomeric nucleoprotein complexes on the ends of viral DNA, termed “intasomes”. INSTIs selectively target intasomes and represent first-line therapies in the clinic. However, the emergence of IN variants resistant to INSTIs is becoming a greater clinical problem. Structural biology approaches can shed light on the mechanisms underlying drug action and resistance, providing useful information for rationally improving the current INSTIs. When complemented with ancillary techniques, such as biochemical activity assays, biophysical thermodynamic and kinetic measurements, cellular virology, and diverse computational approaches including free energy calculations, the structures precisely detail mechanisms of resistance against specific INSTIs and provide guidance for designing and developing novel 3rd generation INSTIs to fight infections. In this proposal, approaches centered around using revolutionary advances in cryo-electron microscopy for structural studies will show how INSTIs interact with their natural drug target, the HIV intasome (both WT and mutant), and elucidate the mechanisms by which resistance to these drugs emerges. There are three Specific Aims that will: (1) extend and build upon current efforts to provide a mechanistic understanding of both why and how select viral resistant variants (VRVs) arise in response to the clinically used drug Dolutegravir (DTG) or the most potent developmental in-house compound that 4d, which is currently under pre-clinical evaluation; (2) broadly identify and analyze novel mechanisms and pathways of drug resistance that arise in response to treatment with 2nd generation drugs, highlighting both primary and compensatory mutations, and providing strategies to predict future variants; (3) select for residual resistant variants arising in response to treatment with novel 3rd generation INSTIs that were synthesized based on the concept of substrate mimicry, many of which effectively inhibit viral resistant variants that arise in response to treatment with 2nd generation clinically used INSTI drugs, and explain mechanisms underlying the superior potency of novel compounds. This work will improve our understanding of an important class of drugs used to treat people living with HIV, identify mechanisms, pathways, and patterns of clinically relevant resistance to INSTIs, and provide specific guidelines for their rational improvement.
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