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Development of efficient strategies for the synthesis of compound libraries of anti-HIV agents that block HIV replication

University of British Columbia

Worldwide, it is estimated that 37 million people are living with HIV/AIDS. Only 35 years ago, the life expectancy for HIV patients was 1-2 years. Fortunately, with the advent of antiretroviral therapy (ART), where different combinations of drugs targeting the HIV proteins are taken, the morbidity rate has dropped very significantly. However, ART fails to eradicate the latent virus pool from infected cells, and this necessitates strict adherence to lifetime treatment schedules. Prolonged ART therapy also leads to issues of toxicity/side effects and drug resistance. These factors underscore the continued need for new drugs, and especially those acting through novel mechanisms of action. My PhD project focused on developing small molecules that inhibit HIV replication through targeting human serine-arginine (SR) protein splicing factors, rather than viral proteins. Once inside the human, HIV is very dependent on human alternative splicing machinery and this explicit reliance may render it sensitive to even slight disturbances in the progression of the disease. Even low doses can thus impair HIV replication while having no or very limited alteration on human splicing events. This work was based on the discovery of IDC16, which perturbs the alternative splicing of HIV mRNA transcripts, and 5350150, which interferes with HIV mRNA transport. Although, these two molecules have anti-HIV activity, they are toxic to human cells. Using parallel synthesis, a library of amide analogues/mimics of IDC16 and 5350150 was prepared and screened. Within the first 2 years of my PhD program, I developed a green and efficient strategy for amide bond formation in which oxo-ester or acid fluoride reacts with N-silylated amines to give di(hetero)arylamides (DHAs) in pure form. This protocol was effective in the production of 92 DHAs in our search for finding new anti-HIV drugs. The screening of the synthesized molecules for their anti-HIV activity led to the discovery of 4.25kk(GPS488) and 4.25ww(GPS491) which are active in both wild type and drug resistant strains, demonstrating that they have a different mechanism of action from the current HIV drugs.drugs.

Text

2022-02-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71656

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/