JE-2147: a dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1.
JE-2147: a dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1.
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JE-2147：一种二肽蛋白酶抑制剂 (PI)，可有效抑制多重 PI 耐药的 HIV-1。
DOI：
10.1073/pnas.96.15.8675
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发表时间：
1999
影响因子：
11.1
通讯作者：
H. Mitsuya
中科院分区：
文献类型：
--
作者：
K. Yoshimura;R. Kato;K. Yusa;M. Kavlick;V. Maroun;A. Nguyen;T. Mimoto;T. Ueno;M. Shintani;J. Falloon;H. Masur;H. Hayashi;J. Erickson;H. Mitsuya
我们设计、合成并鉴定了 JE-2147，这是一种含别苯基去甲他汀的二肽 HIV 蛋白酶抑制剂 (PI)，在体外对多种 HIV-1、HIV-2、猿猴免疫缺陷病毒和各种临床 HIV-1 病毒株具有有效作用。耐药临床 HIV-1 毒株是从 7 名在 32-83 个月后接受 9-11 种不同抗 HIV 治疗失败的患者中分离出来的，具有多种与耐药性相关的氨基酸取代，并且对所有目前可用的抗 HIV 药物都具有高度且始终耐药性。然而，JE-2147 对所有此类耐药菌株均极其有效，IC(50) 值范围为 13-41 nM（与野生型 HIV-1 相比，IC(50) 变化<2 倍）。与对另一种含别苯基去甲他汀的化合物 KNI-272 和其他相关 PI 产生耐药性的 HIV-1 相比，体外对 JE-2147 具有耐药性的 HIV-1 变体的出现明显延迟。结构分析表明，灵活的 P2' 部分的存在对于 JE-2147 对野生型和突变病毒的效力非常重要。这些数据表明，使用柔性组件可能为设计抵抗 PI 耐药 HIV-1 出现的 PI 开辟一条新途径。有必要进一步开发 JE-2147 来治疗携带多重 PI 耐药性 HIV-1 的患者。
We designed, synthesized, and identified JE-2147, an allophenylnorstatine-containing dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months, had a variety of drug-resistance-related amino acid substitutions and were highly and invariably resistant to all of the currently available anti-HIV agents. JE-2147 was, however, extremely potent against all such drug-resistant strains, with IC(50) values ranging from 13-41 nM (<2-fold changes in IC(50) compared with that of wild-type HIV-1). The emergence of JE-2147-resistant HIV-1 variants in vitro was substantially delayed compared with that of HIV-1 resistant to another allophenylnorstatine-containing compound, KNI-272, and other related PIs. Structural analysis revealed that the presence of a flexible P2' moiety is important for the potency of JE-2147 toward wild-type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1. Further development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1 is warranted.