AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor
AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor
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DOI：
10.1016/j.bcp.2005.05.035
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发表时间：
2005-09-01
影响因子：
5.8
通讯作者：
Schols, D
中科院分区：
文献类型：
--
作者：
Hatse, S;Princen, K;Schols, D
趋化因子受体 CCR5 和 CXCR4 作为人类免疫缺陷病毒 (HIV) 的辅助受体发挥作用，是抗 HIV 药物开发的有吸引力的靶点。迄今为止描述的最有效的 CXCR4 拮抗剂是双环类药物。原型化合物 AMD3100 对使用 CXCR4 (X4) 的病毒表现出有效且选择性的抗 HIV 活性，并在 II 期临床试验中对 X4 HIV-1 感染者显示出抗病毒功效。然而，AMD3100 由于其整体正电荷较高，缺乏口服生物利用度。双环酰胺类似物的初步结构-活性关系研究表明，双大环结构是抗 HIV 活性的先决条件。现在，我们报道N-吡啶基亚甲基环酰胺AMD3465缺乏上述结构限制，完全保留了AMD3100的所有生物学特性。与 AMD3100 一样，AMD3465 阻断 CXCL12（天然 CXCR4 配体）和特异性抗 CXCR4 单克隆抗体 12G5 的细胞表面结合。 AMD3465 剂量依赖性地抑制 CXCL12 诱导的细胞内钙信号传导、趋化性、CXCR4 内吞作用和丝裂原激活蛋白激酶磷酸化。与 bicyclam AMD3100 相比，AMD3465 作为 CXCR4 拮抗剂的效果甚至高出 10 倍，同时与 CCR5 没有任何相互作用。正如预期的那样，AMD3465 被证明对 X4 HIV 毒株非常有效（IC50：1-10 nM），但完全无法抑制使用 CCR5（R5）病毒的复制。总之，AMD3465 是一种新型单大环抗 HIV 药物，可特异性阻断 HIV gp120 与 CXCR4 的相互作用。尽管尚未实现口服生物利用度，但与双环类抗生素相比，单环类抗生素的分子电荷减少，体现了在设计可在临床上用作抗 HIV 药物的口服 CXCR4 拮抗剂方面迈出的重要一步。 (c) 2005 Elsevier Inc. 保留所有权利。
The chemokine receptors CCR5 and CXCR4 function as coreceptors for human immunodeficiency virus (HIV) and are attractive targets for the development of anti-HIV drugs. The most potent CXCR4 antagonists described until today are the bicyclams. The prototype compound, AMD3100, exhibits potent and selective anti-HIV activity against CXCR4-using (X4) viruses and showed antiviral efficacy in X4 HIV-1-infected persons in a phase II clinical trial. However, AMD3100 lacks oral bioavailability due to its high overall positive charge. Initial structure-activity relationship studies with bicyclam analogues suggested that the bis-macrocyclic structure was a prerequisite for anti-HIV activity. Now, we report that the N-pyridinylmethylene cyclam AMD3465, which lacks the structural constraints mentioned above, fully conserves all the biological properties of AMD3100. Like AMD3100, AMD3465 blocked the cell surface binding of both CXCL12 (the natural CXCR4 ligand), and the specific anti-CXCR4 monoclonal antibody 12G5. AMD3465 dose-dependently inhibited intracellular calcium signaling, chemotaxis, CXCR4 endocytosis and mitogen-activated protein kinase phosphorylation induced by CXCL12. Compared to the bicyclam AMD3100, AMD3465 was even 10-fold more effective as a CXCR4 antagonist, while showing no interaction whatsoever with CCR5. As expected, AMD3465 proved highly potent against X4 HIV strains (IC50: 1-10 nM), but completely failed to inhibit the replication of CCR5-using (R5) viruses. In conclusion, AMD3465 is a novel, monomacrocyclic anti-HIV agent that specifically blocks the interaction of HIV gp120 with CXCR4. Although oral bioavailability is not yet achieved, the monocyclams, with their decreased molecular charge as compared to the bicyclams, embody an important step forward in the design of oral CXCR4 antagonists that can be clinically used as anti-HIV drugs. (c) 2005 Elsevier Inc. All rights reserved.