HIV-1 is the predominate virus responsible for the AIDs pandemic, accounting for greater than 90% of cases globally. The current treatments for the virus are drug cocktails that target the reverse transcriptase and protease enzymes; however, these proteins mutate rapidly through successive iterations making long term treatment difficult. In this project inhibitors are developed to target the HIV-1 capsid protein (CAN) through the conserved Phe32 active site at the N-terminus of the virus. Inhibitors were synthesized based on a molecular frame developed through computer modelling, experimental testing, and structural activity relationship analysis. Inhibitors were developed building off of a 3,5-bis(trifluoromethyl) substituted aromatic head in three primary series; one series tests functionality of amino acid tail groups, a second series examines hydrophobic effects of the tail group in binding to a hydrophobic pocket near the Phe32 active site of CAN, and a third series explores hydrogen bonding effects of a 2-aminoethanol linker group. 19 novel compounds have been developed and nine new inhibitors have been experimentally tested through {15N-1H HSQC} NMR titrations, achieving a binding affinity of Kd of 26 μM.

Synthesis of HIV-1 capsid protein inhibitors based on SAR analysis

249th National Meeting (2015)

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