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（烷基氨基）哌啶双（杂芳基）哌嗪类似物是1型人类免疫缺陷病毒（HIV-1）耐药分离株的强效、广谱非核苷类逆转录酶抑制剂，并能选择出具有复制表型降低的HIV-1IIIB耐药变体。

(Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes.

作者信息

Olmsted R A, Slade D E, Kopta L A, Poppe S M, Poel T J, Newport S W, Rank K B, Biles C, Morge R A, Dueweke T J, Yagi Y, Romero D L, Thomas R C, Sharma S K, Tarpley W G

机构信息

Cancer and Infectious Diseases Research, Pharmacia & Upjohn, Kalamazoo, Michigan 49001.

出版信息

J Virol. 1996 Jun;70(6):3698-705. doi: 10.1128/JVI.70.6.3698-3705.1996.

DOI:10.1128/JVI.70.6.3698-3705.1996
PMID:8648704
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC190245/
Abstract

The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug-resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA-P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV-1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses.

摘要

（烷基氨基）哌啶双（杂芳基）哌嗪（AAP - BHAPs）是一类新型的1型人类免疫缺陷病毒（HIV - 1）特异性抑制剂，它们是通过对携带关键非核苷逆转录酶抑制剂（NNRTI）耐药性突变的重组逆转录酶（RT）酶以及HIV - 1的NNRTI耐药变体进行靶向筛选而鉴定出来的。对两种最有效的AAP - BHAPs，即U - 95133和U - 104489，针对在HIV - 1 RT第181位携带赋予NNRTI耐药性突变（酪氨酸→半胱氨酸）的体外选择的耐药HIV - 1变体进行表型分析，结果显示这些化合物的90%抑制浓度估计值在亚微摩尔范围内。此外，U - 104489对携带Pro - 236→Leu RT替代的BHA - P耐药HIV - 1MF表现出强效活性，并显著抑制对地拉韦定（BHAP U - 90152T）和齐多夫定均耐药的HIV - 1临床分离株的复制。对AAP - BHAP耐药的HIV - 1IIIB变体的生化和表型特征分析表明，对AAP - BHAPs的高水平耐药是由RT中的Gly - 190→Glu替代介导的，这对病毒体相关RT异二聚体的完整性和酶活性以及这些耐药病毒的复制能力产生了有害影响。

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(Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes.（烷基氨基）哌啶双（杂芳基）哌嗪类似物是1型人类免疫缺陷病毒（HIV-1）耐药分离株的强效、广谱非核苷类逆转录酶抑制剂，并能选择出具有复制表型降低的HIV-1IIIB耐药变体。
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本文引用的文献

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Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents.人类免疫缺陷病毒临床分离株对抗逆转录病毒药物的耐药性。
Antimicrob Agents Chemother. 1993 Jun;37(6):1207-13. doi: 10.1128/AAC.37.6.1207.
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HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy.体内HIV群体动力学：对基因变异、发病机制及治疗的影响
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In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors.对多种蛋白酶抑制剂耐药的HIV-1变体在体内的出现。
Nature. 1995 Apr 6;374(6522):569-71. doi: 10.1038/374569a0.
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Activity of a novel quinoxaline derivative against human immunodeficiency virus type 1 reverse transcriptase and viral replication.一种新型喹喔啉衍生物对人免疫缺陷病毒1型逆转录酶及病毒复制的活性
Antimicrob Agents Chemother. 1993 Aug;37(8):1659-64. doi: 10.1128/AAC.37.8.1659.
6
A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group.HIV-1逆转录酶非核苷抑制剂L-697,661的短期临床评估。L-697,661研究小组
N Engl J Med. 1993 Oct 7;329(15):1065-72. doi: 10.1056/NEJM199310073291502.
7
pol mutations conferring zidovudine and didanosine resistance with different effects in vitro yield multiply resistant human immunodeficiency virus type 1 isolates in vivo.赋予齐多夫定和去羟肌苷耐药性且在体外具有不同效应的pol突变，在体内产生多重耐药的1型人类免疫缺陷病毒分离株。
Antimicrob Agents Chemother. 1993 Jul;37(7):1480-7. doi: 10.1128/AAC.37.7.1480.
8
Treatment of human immunodeficiency virus type 1 (HIV-1)-infected cells with combinations of HIV-1-specific inhibitors results in a different resistance pattern than does treatment with single-drug therapy.用1型人类免疫缺陷病毒（HIV-1）特异性抑制剂组合治疗HIV-1感染的细胞，会产生与单药治疗不同的耐药模式。
J Virol. 1993 Sep;67(9):5353-9. doi: 10.1128/JVI.67.9.5353-5359.1993.
9
U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication.U - 90152，一种强效的1型人类免疫缺陷病毒复制抑制剂。
Antimicrob Agents Chemother. 1993 May;37(5):1127-31. doi: 10.1128/AAC.37.5.1127.
10
A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors.对双（杂芳基）哌嗪耐药的1型人类免疫缺陷病毒逆转录酶中的一种突变，该突变使病毒对其他非核苷抑制剂的敏感性增加。
Proc Natl Acad Sci U S A. 1993 May 15;90(10):4713-7. doi: 10.1073/pnas.90.10.4713.