Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine.
Twenty-five years ago, nucleoside analog 3'-azidothymidine (AZT) was shown to efficiently block the replication of HIV in cell culture. Subsequent studies demonstrated that AZT acts via the selective inhibition of HIV reverse transcriptase (RT) by its triphosphate metabolite. These discoveries have established the first class of antiretroviral agents: nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs). Over the years that followed, NRTIs evolved into the main component of antiretroviral drug combinations that are now used for the treatment of all populations of HIV infected patients. A total of thirteen NRTI drug products are now available for clinical application: eight individual NRTIs, four fixed-dose combinations of two or three NRTIs, and one complete fixed-dose regimen containing two NRTIs and one non-nucleoside RT inhibitor. Multiple NRTIs or their prodrugs are in various stages of clinical development and new potent NRTIs are still being identified through drug discovery efforts. This article will review basic principles of the in vitro and in vivo pharmacology of NRTIs, discuss their clinical use including limitations associated with long-term NRTI therapy, and describe newly identified NRTIs with promising pharmacological profiles highlighting those in the development pipeline. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, volume 85, issue 1, 2010.
Cihlar
Tomas
T
Department of Biology, Gilead Sciences, Inc., 362 Lakeside Drive, Foster City, CA 94404, USA. tomas.cihlar@gilead.com
Ray
Adrian S
AS
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology / Q000627:therapeutic use*; D009711:Nucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D009705:Nucleosides; D009711:Nucleotides; D015215:Zidovudine; D054303:HIV Reverse Transcriptase