The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor
The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor
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DOI：
10.1124/mol.104.008565
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发表时间：
2005-04-01
影响因子：
3.6
通讯作者：
Kenakin, T
中科院分区：
文献类型：
--
作者：
Watson, C;Jenkinson, S;Kenakin, T
4-{[4-({(3R)-1-丁基-3-[（R)-环己基（羟基）甲基]-2,5二氧基-1,4,9-三氮唑斯匹罗[5.5]11 -9-基}甲基）苯基]氧}苯甲酸盐酸盐（873140）是一种有效的CCR5受体非竞争性变构拮抗剂(pK(B) = 8.6 +/- 0.07；95% CI, 8.5 - 8.8)，同时对HIV-1具有有效的抗病毒作用。本文将873140与其他4种CCR5非竞争性变构拮抗剂的受体作用机制进行了比较。虽然(Z)-（4-溴苯基）{1'-[（2,4-二甲基-1-氧化-3-吡啶基）羰基]4'-甲基-1,4'-双哌酸-4-基}甲烷-o -乙基肟（SCH - c; SCH 351125）， 4,6-二甲基-5-{[4-甲基-4-((3S)-3-甲基-4-{（1R)-2-（甲基）-1-[4-（三氟甲基）苯基]乙基}-1-哌酸基）-1-哌酸基]羰基}嘧啶(SCH -d；SCH 417,690), 4,4二氟-N-((1S)-3-{（3-内do)-3-[3-甲基-5-（1-甲基乙基）4h -1,2,4-三唑-4-基]-8-氮杂环基[3.2.1]辛-8-基}-1-苯基-丙基）环己烷酰胺（UK-427,857）和N，N-二甲基-N-[[[2-（4-甲基苯基）-6,7-二氢- 5h -苯并环庚-8-基]羰基]氨基]苄基]四氢- 2h -吡喃-4-氯化铵（TAK779）阻断了趋化因子I-125-MIP-1 α（也称为I-125-CCL3， I-125-LD78）和I-125-RANTES （I-125-CCL5）的结合。873140是I-125-RANTES（激活正常T细胞表达和分泌）结合的无效拮抗剂（但确实阻断了I-125-MIP-1 α的结合）。此外，873140阻断CCL5激活CCR5的钙反应效应（RANTES）（与其他拮抗剂一样），表明其功能阻断和与该拮抗剂的结合存在独特的差异。873140对CCR5的拮抗作用是饱和的和探针依赖性的，与变构作用机制一致。873140对CCR5的阻断非常持久，逆转速率常数< 0.004 h(-1) （t(1/2) > 136 h）。873140与其他四种变构拮抗剂的联合给药研究得出的数据与这五种拮抗剂与CCR5受体上的共同变构位点结合的观点一致。尽管这些配体可能具有共同的结合位点，但它们对受体的变构作用不同，这可以从它们对I-125-RANTES结合的不同影响中看出。这个想法是在使用这些药物的顺序来克服HIV病毒在临床的耐药性方面进行讨论。
4-{[4-({(3R)-1-Butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140) is a potent noncompetitive allosteric antagonist of the CCR5 receptor (pK(B) = 8.6 +/- 0.07; 95% CI, 8.5 to 8.8) with concomitantly potent antiviral effects for HIV-1. In this article, the receptor-based mechanism of action of 873140 is compared with four other noncompetitive allosteric antagonists of CCR5. Although (Z)-(4-bromophenyl){1'-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]4'-methyl-1,4'-bipiperidin-4-yl}methanone O-ethyloxime (Sch-C; SCH 351125), 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R)-2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinyl]carbonyl}pyrimidine (Sch-D; SCH 417,690), 4,4difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenyl-propyl)cyclohexanecarboxamide (UK-427,857), and N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclo-hepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride (TAK779) blocked the binding of both chemokines I-125-MIP-1 alpha (also known as I-125-CCL3, I-125-LD78) and I-125-RANTES (I-125-CCL5), 873140 was an ineffectual antagonist of I-125-RANTES (regulated on activation normal T cell expressed and secreted) binding (but did block binding of I-125-MIP-1 alpha). Furthermore, 873140 blocked the calcium response effects of CCR5 activation by CCL5 ( RANTES) (as did the other antagonists), indicating a unique divergence of blockade of function and binding with this antagonist. The antagonism of CCR5 by 873140 is saturable and probe-dependent, consistent with an allosteric mechanism of action. The blockade of CCR5 by 873140 was extremely persistent with a rate constant for reversal of < 0.004 h(-1) (t(1/2) > 136 h). Coadministration studies of 873140 with the four other allosteric antagonists yielded data that are consistent with the notion that all five of these antagonists bind to a common allosteric site on the CCR5 receptor. Although these ligands may have a common binding site, they do not exert the same allosteric effect on the receptor, as indicated by their differential effects on the binding of I-125-RANTES. This idea is discussed in terms of using these drugs sequentially to overcome HIV viral resistance in the clinic.