HIV-1/AIDS is a condition that affects over 35 million people. The virus infects immune system cells, mainly CD4 T-cells, and leaves the host susceptible to opportunistic infections that are lethal without a sufficient immune response. Current treatments slow the progression of the disease but do not eliminate infection. Problems with current treatments include clinical toxicities from long-term use of pharmaceuticals and viral mutations leading to drug-resistant strains. A proposed mechanism to circumvent this issue and allow for a more efficient inhibition involves the use of two nucleoside or nucleotide analogs. The first nucleotide analog is expected to be incorporated and temporarily halt synthesis due to the lack of a 3’-OH. When the second analog is brought into proximity to the first by the HIV-RT, the analogs react together and covalently link to the HIV-RT enzyme and halt its motion. Some benefits of covalent inhibition are as follows; the enzyme cannot dissociate from the template and synthesize new strands, the template cannot be released and bind to another enzyme for transcription, and the specificity of the mechanism allows for more precise targeting of the HIV-RT. Many of the current pharmaceuticals exhibit promiscuity and can affect other biological mechanisms in the host, such as the activity of mitochondrial DNA polymerase gamma, which leads to some of the observed toxicities. By having a two-component system for HIV-RT inhibition, there should be a minimization of resistant strains via mutation and a decrease in toxicity due to increased specificity.

Synthesis of nucleoside analogs for inhibition of HIV-1 RT

2019 Spring National Meeting

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