A Conformationally Frozen Peptoid Boosts CXCR4 Affinity and Anti-HIV Activity
A Conformationally Frozen Peptoid Boosts CXCR4 Affinity and Anti-HIV Activity
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DOI：
10.1002/anie.201202090
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Kessler, Horst
中科院分区：
文献类型：
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作者：
Demmer, Oliver;Frank, Andreas O.;Kessler, Horst
趋化因子受体亚型CXCR4属于G蛋白偶联受体(GPCRs)，与其天然配体CXCL12(或SDF-1)一起，是人体信号系统的中枢部分。CXCR4的功能范围从胚胎发育过程中的干细胞转运，到心血管、造血和大脑发育，到神经系统和免疫系统的信号传递。[1-6]此外，CXCR4是人类免疫缺陷病毒(HIV)用于细胞进入的两个主要辅助受体之一，使用CXCR4的病毒对艾滋病的发病至关重要。[7，8]因此，CXCR4是多种疾病的有价值的治疗选择，如炎症、癌症、[9]和HIV/AIDS。[10]CXCR4拮抗剂AMD3100(MOZOBIL)最近被批准作为一种干细胞动员药物，为进一步开发针对CXCR4相关疾病的化合物铺平了道路。[1，11]然而，目前FDA批准的抗HIV药物中没有一种针对CXCR4受体。最有趣的一类CXCR4拮抗剂来自自然产生的双环肽Polyphusin II，它被逐步修饰为单环T140。[12]单环T140及其衍生物是反向激动剂，因此与其他作为部分激动剂的CXCR4拮抗剂相比，提供了对CXCR4拮抗剂的选择性优势例如，AMD3100.[13，14]在我们努力开发高亲和力CXCR4配体作为适合分子成像的探针[15-17]的过程中，我们通过基于配体的设计，使用构象考虑和构效关系(SAR)来扩展我们的研究。在这里，我们描述了具有皮摩尔亲和力的CXCR4拮抗剂，它们的结合模式，以及它们抑制细胞感染HIV的能力。Fujii等人的开创性工作。证明了多肽CXCR4拮抗剂T140可以从14个氨基酸缩小为头尾环化的五肽，结合亲和力(IC50)为8 nm(FC131；1a)。[18]该肽被进一步修饰为N-甲基化类似物环(-d-Tyr 1-d-[NME]Arg2-Arg3-Na4-Gly5-)(NAL=L-3-(2-萘基)丙氨酸)1b，从而获得更高的亲和力(IC50=3 nm，图1)。[19]这是迄今为止已知的与环五肽化合物最高的CXCR4结合亲和力。
The chemokine receptor subtype CXCR4 belongs to the G-protein coupled receptors (GPCRs) and is, together with its natural ligand CXCL12 (or SDF-1), a central part of the signaling system in the human body. Its functions range from stem-cell trafficking during embryogenesis, through cardiovascular, hematopoietic, and brain development, to signaling in the nervous and immune system.[1–6] Furthermore, CXCR4 is one of two major coreceptors used by the human immunodeficiency virus (HIV) for cell entry and CXCR4-using viruses are critical for the pathogenesis of AIDS.[7, 8] Hence, CXCR4 represents a valuable therapeutic option for multiple diseases, such as inflammation, cancer,[9] and HIV/AIDS.[10] The recent approval of the CXCR4 antagonist AMD3100 (Mozobil) as a drug for stem-cell mobilization paves the way for development of further compounds that target CXCR4 related diseases.[1, 11] However at present, none of the FDA-approved anti-HIV drugs target the CXCR4 receptor.One of the most interesting classes of CXCR4 antagonists is derived from the naturally occurring bicyclic peptide polyphemusin II which was modified in a stepwise fashion into monocyclic T140.[12] The monocyclic T140 and its derivatives are inverse agonists and therefore additionally offer the advantage of selectivity towards CXCR4 over other CXCR4 antagonists which function as partial agonists, for example, AMD3100.[13, 14] In our efforts to develop highaffinity CXCR4 ligands as suitable probes for molecular imaging [15–17] we extended our studies through ligand-based design using conformational considerations and structure–activity relationships (SAR). Herein we describe CXCR4 antagonists with picomolar affinity, their binding mode, and their capacity to inhibit the HIV infection of cells. The pioneering work of Fujii et al. demonstrated that the peptidic CXCR4 antagonist T140 can be downsized from 14 amino acids into a head-to-tail cyclized pentapeptide with a binding affinity (IC50) of8nm (FC131; 1a).[18] This peptide was further modified into the N-methylated analogue cyclo (-d-Tyr 1-d-[NMe] Arg2-Arg3-Nal4-Gly5-)(Nal= l-3-(2-naphthyl) alanine) 1b resulting in even higher affinity (IC50= 3 nm, Figure 1).[19] This is the highest CXCR4 binding affinity known to date for compounds with the cyclopentapeptide scaffold.