Post-Catalytic Complexes with Emtricitabine or Stavudine and HIV-1 Reverse Transcriptase Reveal New Mechanistic Insights for Nucleotide Incorporation and Drug Resistance
The U.S. Department of Energy's Office of Scientific and Technical Information
Since its discovery in the early 1980s, the human immunodeficiency virus 1 (HIV-1) has been a major health issue with nearly 38.0 million people infected globally in 2019 according to the WHO [1]. Despite extensive research efforts, neither a cure nor a vaccine for HIV-1 infection has been discovered yet. However, a breakthrough has been achieved with the highly active antiretroviral therapy (HAART), which significantly improves the life expectancy for patients with acquired immune deficiency syndrome (AIDS).
Two of the six classes of the United States Food and Drug Administration (FDA) approved drugs for HIV-1 treatment target the reverse transcriptase (RT) protein, an enzyme critical for the replication cycle of HIV-1 [2]. These two classes are nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). While NNRTIs are allosteric inhibitors that alter the chemical catalysis rate limiting step through conformational changes [3,4], NRTIs mimic nucleotides that bind to the active site of RT. Since NRTIs lack the 30 -hydroxyl group necessary for chain elongation, their incorporation results in termination of the viral DNA transcription [5]. NRTIs are essential components of HAART and part of almost all FDA approved combination therapies for the treatment and protection of an infection with HIV. However, some FDA-approved NRTIs are now rarely prescribed (e.g., stavudine (d4T)) or discontinued (e.g., zalcitabine (ddC)) due to their off-target toxicity.
