Hatse Sigrid, Princen Katrien, De Clercq Erik, Rosenkilde Mette M, Schwartz Thue W, Hernandez-Abad Pedro E, Skerlj Renato T, Bridger Gary J, Schols Dominique
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
Biochem Pharmacol. 2005 Sep 1;70(5):752-61. doi: 10.1016/j.bcp.2005.05.035.
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.
趋化因子受体CCR5和CXCR4作为人类免疫缺陷病毒（HIV）的共受体发挥作用，是抗HIV药物研发的有吸引力的靶点。迄今为止描述的最有效的CXCR4拮抗剂是双环胺类化合物。原型化合物AMD3100对使用CXCR4的（X4）病毒表现出强效且选择性的抗HIV活性，并在一项II期临床试验中对X4 HIV-1感染患者显示出抗病毒疗效。然而，AMD3100由于其高总体正电荷而缺乏口服生物利用度。对双环胺类似物的初步构效关系研究表明，双大环结构是抗HIV活性的先决条件。现在，我们报道了缺乏上述结构限制的N-吡啶基亚甲基环胺AMD3465完全保留了AMD3100的所有生物学特性。与AMD3100一样，AMD3465阻断了CXCL12（天然CXCR4配体）以及特异性抗CXCR4单克隆抗体12G5的细胞表面结合。AMD3465剂量依赖性地抑制由CXCL12诱导的细胞内钙信号传导、趋化性、CXCR4内吞作用和丝裂原活化蛋白激酶磷酸化。与双环胺AMD3100相比，AMD3465作为CXCR4拮抗剂的效力甚至高10倍，同时与CCR5没有任何相互作用。正如预期的那样，AMD3465对X4 HIV毒株显示出高效力（IC50：1 - 10 nM），但完全无法抑制使用CCR5的（R5）病毒的复制。总之，AMD3465是一种新型的单大环抗HIV药物，它特异性地阻断HIV gp120与CXCR4的相互作用。尽管尚未实现口服生物利用度，但与双环胺相比分子电荷降低的单环胺类化合物在可临床用作抗HIV药物的口服CXCR4拮抗剂的设计中迈出了重要的一步。
