A human immunodeficiency virus type 1 (HIV-1) retrovirus was identified as the agent causing acquired immunodeficiency syndrome (AIDS), one of history's most detrimental infectious diseases. HIV contains dual receptors CCR5 and CXCR4, responsible for activating the virus to hijack the cell's machinery; CCR5 receptors are generally responsible for viral transmission, and CXCR4 or both (dual tropic) emerge later during disease progression. Therefore, a treatment to prevent or reduce the severity of AIDS is important. Multiple drugs, such as protease and integrase inhibitors that target and inhibit important events in the HIV life cycle, called antiretroviral therapy (ARTs), have been introduced. While many drugs that target various stages of the HIV lifecycle have been discovered, very few prevent viral entry into immune cells. One FDA-approved drug, maraviroc, inhibits CCR5 but not CXCR4. Further research is therefore needed to increase the diversity of HIV drugs in order to minimize drug resistance.
Using computational screening, Professor Pedzisa has identified a compound predicted to bind to both CCR5 and CXCR4 (Hit 1). We plan on synthesizing and purifying Hit 1 using various organic syntheses procedures such as column chromatography, rotary evaporation, TLC, gravity, and vacuum filtration and analyzing through Mass spectrometry and NMR. Ribavirin is an approved compound to treat an opportunistic infection of HIV and is the starting material of our reaction. So far, we have protected Ribavirin as an acetonide (1) currently being re-oxidized into a carboxylic acid (2). Then, another fragment (3) necessary in the synthesis will be further coupled by Boc deprotonation to afford an analog (4). Finally, the two fragments produced will be coupled using HATU and deprotected with a catalyst pTSA (5) to finally give the final target compound, Hit 1. Previously, we had gone as far as Boc deprotection, but the compound was impure and purification by column chromatography proved challenging. We are currently resynthesizing the target using alternative oxidation methods.
Our target compound (and analogs) should help us determine if it binds to both CCR5 and CXCR4 as predicted by the our computational screen. This should pave way for more options for ART against HIV.