Resistance pattern of human immunodeficiency virus type 1 reverse transcriptase to quinoxaline S-2720.

Abstract

The human immunodeficiency virus type 1 (HIV-1)-specific reverse transcriptase (RT) inhibitor quinoxaline S-2720 showed a more-potent inhibitory effect on HIV-1-induced cytopathicity in CEM cells than either nevirapine, pyridinone L-697,661, bis-heteroarylpiperazine (BHAP) U-88204, TSAO ([2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5 "- (4-amino-1",2"-oxathiole-2",2"-dioxide)-N3-ethylthymine, or 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4-benzodiazepin-2(I H)-one (TIBO) R82913. The quinoxaline derivative was also markedly more inhibitory to the mutant HIV-1 strains containing in their RT Ile-100, Asn-103, Ala-106, Lys-138, Cys-181, or His-188 substitutions than were the other HIV-1-specific RT inhibitors. Moreover, quinoxaline S-2720 totally prevented HIV-1 infection and emergence of drug-resistant mutant virus strains in CEM cell cultures at concentrations (i.e., 0.35 microM) that are 10- to 25-fold lower than those required for BHAP U-88204 and nevirapine to knock out the virus. Also, the concentration-response curve for S-2720 was markedly steeper than for BHAP and nevirapine, as reflected by the ratio of the 95% to the 50% antivirally effective concentration. Lower concentrations of quinoxaline dominantly lead to the appearance of the Ala-106 RT mutation, causing low-level resistance to the compound. At higher quinoxaline concentrations, the Glu-190 RT and/or the Cys-181 RT mutation is added to the Ala-106 mutation, whereas at the highest quinoxaline concentrations, the Ala-106 mutation tends to disappear from the virus pool, leaving the Glu-190 RT and Cys-181 RT mutations as the only mutations conferring high-level resistance to the compound.

• Authors: J Balzarini, A Karlsson, C Meichsner, A Paessens, G Riess, E De Clercq, J P Kleim
• Journal: Journal of virology (J Virol) Vol. 68 Issue 12 Pg. 7986-92 (Dec 1994) ISSN: 0022-538X [Print] United States
• PMID: 7525984 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• DNA Primers
• Quinoxalines
• Reverse Transcriptase Inhibitors
• S 2720
• HIV Reverse Transcriptase
• RNA-Directed DNA Polymerase

Topics

• Amino Acid Sequence
• Antiviral Agents (pharmacology)
• Base Sequence
• Cell Line
• DNA Primers
• Drug Resistance, Microbial
• Genes, Viral
• Giant Cells (drug effects)
• HIV Reverse Transcriptase
• HIV-1 (drug effects, enzymology, physiology)
• Humans
• Microbial Sensitivity Tests
• Molecular Sequence Data
• Mutagenesis, Site-Directed
• Point Mutation
• Polymerase Chain Reaction
• Quinoxalines (pharmacology)
• RNA-Directed DNA Polymerase (biosynthesis, genetics)
• Reverse Transcriptase Inhibitors