The Relative Activity of "Function Sparing" HIV-1 Entry Inhibitors on Viral Entry and CCR5 Internalization: Is Allosteric Functional Selectivity a Valuable Therapeutic Property?
The Relative Activity of "Function Sparing" HIV-1 Entry Inhibitors on Viral Entry and CCR5 Internalization: Is Allosteric Functional Selectivity a Valuable Therapeutic Property?
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DOI：
10.1124/mol.108.052555
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发表时间：
2009-03-01
影响因子：
3.6
通讯作者：
Kenakin, Terry P.
中科院分区：
文献类型：
--
作者：
Muniz-Medina, Vanessa M.;Jones, Stacey;Kenakin, Terry P.
比较了趋化因子（C-C基序）受体5（CCR 5）受体的六种变构HIV-1进入抑制剂调节剂作为HIV-1进入[人骨肉瘤（HOS）细胞和外周血单核细胞（PBMC）感染]抑制剂和趋化因子（C-C基序）配体3样1[CCL 3L 1]介导的CCR 5内化拮抗剂的效力。后一种活性已被鉴定为CCL 3L 1在延长HIV-1感染后的存活中的有益作用（Science 307：1434-1440，2005）。这些调节剂的变构性质进一步得到证实，发现阻断CCL 3L 1介导的内化相对于HIV-1进入的相对效力存在58倍（HOS细胞）和282倍（PBMC）差异。对于CCR 5调节剂，发现马拉韦罗、维克韦罗、aplaviroc、Sch-C、TAK 652和TAK 779的该比率存在统计学显著差异。例如，尽管TAK 652作为HIV-1抑制剂的效力是其13倍（超过对CCL 3L 1介导的CCR 5内化的阻断），但Sch-C的效力比例是相反的（对CCR 5介导的内化的效力是HIV-1进入的22倍）。通过这些配体对CCR 5内化的不可逾越的拮抗作用的定量分析表明，它们都降低了CCL 3L 1对CCR 5内化的功效。伴随着aplaviroc、maraviroc和vicriviroc的最大响应的抑制的相对小幅度的右旋位移表明这些调节剂对CCL 3L 1亲和力具有最小的影响，尽管可能的受体储备效应模糊了对该效应的完整解释。这些数据进行了讨论，在涉及变构抑制剂的艾滋病的HIV-1进入抑制治疗中保留天然CCR 5趋化因子功能的可能益处。
Six allosteric HIV-1 entry inhibitor modulators of the chemokine (C-C motif) receptor 5 (CCR5) receptor are compared for their potency as inhibitors of HIV-1 entry [infection of human osteosarcoma (HOS) cells and peripheral blood mononuclear cells (PBMC)] and antagonists of chemokine (C-C motif) ligand 3-like 1[CCL3L1]-mediated internalization of CCR5. This latter activity has been identified as a beneficial action of CCL3L1 in prolonging survival after HIV-1 infection (Science 307: 1434-1440, 2005). The allosteric nature of these modulators was further confirmed with the finding of a 58-fold (HOS cells) and 282-fold (PBMC) difference in relative potency for blockade of CCL3L1-mediated internalization versus HIV-1 entry. For the CCR5 modulators, statistically significant differences in this ratio were found for maraviroc, vicriviroc, aplaviroc, Sch-C, TAK652, and TAK779. For instance althrough TAK652 is 13-fold more potent as an HIV-1 inhibitor (over blockade of CCL3L1-mediated CCR5 internalization), this ratio of potency is reversed for Sch-C (22-fold more potent for CCR5-mediated internalization over HIV-1 entry). Quantitative analyses of the insurmountable antagonism of CCR5 internalization by these ligands suggest that all of them reduce the efficacy of CCL3L1 for CCR5 internalization. The relatively small magnitude of dextral displacement accompanying the depression of maximal responses for aplaviroc, maraviroc and vicriviroc suggests that these modulators have minimal effects on CCL3L1 affinity, although possible receptor reserve effects obscure complete interpretation of this effect. These data are discussed in terms of the possible benefits of sparing natural CCR5 chemokine function in HIV-1 entry inhibition treatment for AIDS involving allosteric inhibitors.