Abstract
Reverse transcriptase (RT) from the human immunodeficiency virus continues to be an attractive drug target for antiretroviral therapy. June 2022 will commemorate the 30th anniversary of the first Human Immunodeficiency Virus (HIV) RT crystal structure complex that was solved with non-nucleoside reverse transcriptase inhibitor nevirapine. The release of this structure opened opportunities for designing many families of non-nucleoside reverse transcriptase inhibitors (NNRTIs). In paying tribute to the first RT-nevirapine structure, we have developed several compound classes targeting the non-nucleoside inhibitor binding pocket of HIV RT. Extensive analysis of crystal structures of RT in complex with the compounds informed iterations of structure-based drug design. Structures of seven additional complexes were determined and analyzed to summarize key interactions with residues in the non-nucleoside inhibitor binding pocket (NNIBP) of RT. Additional insights comparing structures with antiviral data and results from molecular dynamics simulations elucidate key interactions and dynamics between the nucleotide and non-nucleoside binding sites.
Highlights
The HIV-1 (Human Immunodeficiency Virus) is a member of the retroviral family which contains a single-stranded RNA genome and is the major etiological agent involved in the development of acquired immunodeficiency syndrome or AIDS
nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) are commonly used for prevention and treatment of HIV
Structure optimization of NNRTIs is still important for designing new compounds that can overcome physiochemical property and resistance limitations
Summary
The HIV-1 (Human Immunodeficiency Virus) is a member of the retroviral family which contains a single-stranded RNA genome and is the major etiological agent involved in the development of acquired immunodeficiency syndrome or AIDS. The World Health Organization estimates that in 2019 over 40 million people worldwide were infected. The most recent CDC report estimates that in the US over 1.2 million people are infected including about 13% who are unaware of their infections. The number of people living with HIV has increased, while the annual number of new infections has remained relatively stable. The pace of new infections, at 50,000 per year, continues at far too high a level, among certain socio-economic groups. Structural Studies and SAR for Novel NNRTIs
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