Stevens Miguel, Pannecouque Christophe, De Clercq Erik, Balzarini Jan
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Antimicrob Agents Chemother. 2003 Sep;47(9):2951-7. doi: 10.1128/AAC.47.9.2951-2957.2003.
A new class of pyridine oxide derivatives as inhibitors of human immunodeficiency virus type 1 (HIV-1) and/or HIV-2 replication in cell culture has been identified. The compounds, which specifically inhibit HIV-1, behave as typical nonnucleoside reverse transcriptase inhibitors (NNRTIs). The most active congener of this group, JPL-133 (UC-B3096), has a 50% effective concentration of 0.05 microg/ml for HIV-1(III(B)) with a selectivity index of approximately 760 in CEM cell cultures. However, the cytostatic activity of most pyridine oxide derivatives highly depended on the nature of the cell line. All compounds, including those pyridine oxide derivatives that inhibit both HIV-1 and HIV-2 replication, select for NNRTI-characteristic mutations in the HIV-1 reverse transcriptase of HIV-infected cell cultures (i.e., Lys103Asn, Val108Ile, Glu138Lys, Tyr181Cys and Tyr188His). These amino acid mutations emerged mostly through transition of guanine to adenine or adenine to guanine in the corresponding codons of the reverse transcriptase (RT) gene. The HIV-1-specific pyridine oxide derivatives lost their antiviral activity against HIV-1 strains containing these mutations in the RT. However, most compounds retained pronounced antiviral potency against virus strains that contained other NNRTI-characteristic RT mutations, such as Leu100Ile and Val179Asp. Furthermore, the complete lack of inhibitory activity of the pyridine oxide derivatives against recombinant HIV-2 RT and partial retention of anti-HIV-1 activity against HIV-1 strains that contain a variety of HIV-1-characteristic mutations suggest that the pyridine oxide derivatives must have a second target of antiviral action independent from HIV-1 RT.
已鉴定出一类新型吡啶氧化物衍生物可作为细胞培养中人类免疫缺陷病毒1型（HIV-1）和/或HIV-2复制的抑制剂。这些化合物特异性抑制HIV-1，表现为典型的非核苷类逆转录酶抑制剂（NNRTIs）。该组中活性最高的同系物JPL-133（UC-B3096）对HIV-1(III(B))的50%有效浓度为0.05微克/毫升，在CEM细胞培养中的选择性指数约为760。然而，大多数吡啶氧化物衍生物的细胞生长抑制活性高度依赖于细胞系的性质。所有化合物，包括那些抑制HIV-1和HIV-2复制的吡啶氧化物衍生物，都会在HIV感染细胞培养物的HIV-1逆转录酶中选择NNRTI特征性突变（即Lys103Asn、Val108Ile、Glu138Lys、Tyr181Cys和Tyr188His）。这些氨基酸突变大多是通过逆转录酶（RT）基因相应密码子中鸟嘌呤向腺嘌呤或腺嘌呤向鸟嘌呤的转换出现的。HIV-1特异性吡啶氧化物衍生物对RT中含有这些突变的HIV-1毒株失去了抗病毒活性。然而，大多数化合物对含有其他NNRTI特征性RT突变（如Leu100Ile和Val179Asp）的病毒毒株仍保留显著的抗病毒效力。此外，吡啶氧化物衍生物对重组HIV-2 RT完全缺乏抑制活性，而对含有多种HIV-1特征性突变的HIV-1毒株部分保留抗HIV-1活性，这表明吡啶氧化物衍生物必须有一个独立于HIV-1 RT的抗病毒作用的第二个靶点。
