[Chemical characteristics, mechanism of action and antiviral activity of etravirine].
Etravirine (ETR) is a diarylpyrimidine derivative with a polycyclic molecule composed of 3 aromatic rings with single bonds between the rings (C(20)H(15)BrN(60)). The drug acts through a mechanism of noncompetitive inhibition on binding to a hydrophobic binding pocket, very close to the active center of the enzyme, provoking an allosteric transition to a conformation that distorts its structure and impedes DNA polymerization. The 3 rings with single bonds between the rings confer the molecule with great fl exibility and torsion. Because of these characteristics, etravirine can adapt to conformational changes in the binding pocket, including a large number of the conformations provoked by the resistance mutations that appear after failure to regimens that include efavirenz or nevirapine. This specific chemical structure largely explains the drug's distinguishing features in terms of its antiviral potency and high genetic barrier. ETR is a highly active molecule against HIV-1. This drug has a high genetic barrier to resistance and has demonstrated antiviral activity against a wide panel of recombinant viruses that incorporate resistance mutations to first-generation non-nucleoside analogues. Equally, ETR has demonstrated efficacy against several subtypes of the M group of HIV-1 (A, B, C, D, F and H, and recombinant forms CRF01_AE, CRF02_AG, CRF05_DF), as well as against isolates of HIV-1 group O. ETR, as the rest of non-nucleoside analogues, does not have demonstrated antiviral activity against HIV-2.
García
Federico García
FG
Hospital Universitario San Cecilio, Granada, España. fegarcia@ugr.es
Estévez
Marta Alvarez
MA
Suay
Vicente Guillot
VG
D000495:Allosteric Site / Q000187:drug effects; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D015394:Molecular Structure; D009570:Nitriles; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase