title: Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future.
abstract: Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have become an inherent ingredient of the drug combination schemes that are currently used in the treatment of human immunodeficiency virus type 1 (HIV-1) infections. Starting from the 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine (HEPT) and 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) derivatives, numerous classes of compounds have been described as NNRTIs. Only three compounds have so far been approved for clinical use: nevirapine, delavirdine, and efavirenz. NNRTIs are notorious for rapidly leading to virus-drug resistance development, primarily based on the emergence of the K103N and Y181C mutations in the HIV-1 RT. Newer NNRTIs, such as capravirine, dapivirine (TMC 125), and DPC 083, are resilient to these 'NNRTI' mutations, and, therefore, offer considerable promise as future anti-HIV-1 drugs. NNRTIs are targeted at a specific 'pocket' binding site within the HIV-1 RT, that is distinct from, but both spatially and functionally related to, the catalytic site, where the nucleoside RT inhibitors (NRTIs) and nucleotide RT inhibitors (NtRTIs) interact. NNRTIs have acquired a definitive position, as part of a combination regimen with NRTIs and NtRTIs, in the first-line treatment of HIV-1 infections.
authors.affiliation: Rega Institute for Medical Research, K.U. Leuven, B-3000 Leuven. erik.declercq@rega.kuleuven.ac.be
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000818:Animals; D015658:HIV Infections / Q000188:drug therapy / Q000201:enzymology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase