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Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Past, Present, and Future
Author(s) -
De Clercq Erik
Publication year - 2004
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200490012
Subject(s) - efavirenz , nevirapine , reverse transcriptase , virology , nucleoside reverse transcriptase inhibitor , chemistry , nucleoside , human immunodeficiency virus (hiv) , zidovudine , reverse transcriptase inhibitor , biology , antiretroviral therapy , stereochemistry , rna , biochemistry , viral load , viral disease , gene
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(1 H )‐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.