Selective, tight-binding inhibitors of integrin α4β1 that inhibit allergic airway responses
Selective, tight-binding inhibitors of integrin α4β1 that inhibit allergic airway responses
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DOI：
10.1021/jm980673g
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发表时间：
1999-03-11
影响因子：
7.3
通讯作者：
Adams, SP
中科院分区：
文献类型：
--
作者：
Lin, KC;Ateeq, HS;Adams, SP
整合素α4β1介导白细胞募集、激活、介质释放和细胞凋亡抑制，在炎症病理生理学中发挥重要作用。本发明描述了基于细胞纤维连接蛋白选择性剪接连接段1(CS-1)肽的Leu-Asp-Val(LDV)序列的高亲和力、选择性的α4β1抑制剂，其采用了一种新的N端肽“帽”策略。BIO-1211类似于10(6)倍的起始肽，并表现出紧密结合的性质(k(OFF)=1.4×10(-4)S(-1)，K-D=70 pm，这对于一个非共价的蛋白质受体小分子抑制剂来说是一个了不起的发现。BIO-1211对活化形式的α4β1的选择性也是200倍，它刺激了整合素β1亚单位上配体诱导的表位的表达，这一特性与受体的配体结合部位的占有率一致。用3毫克BIO-1211雾化吸入过敏性绵羊可抑制抗原攻击后早期和晚期的呼吸道反应，并防止对氨基甲胆碱的非特异性呼吸道高反应性的发展。这些结果表明，除了Arg-Gly-Asp(RGD)外，可以发现对整合素具有主要特异性的高选择性和强大的小分子拮抗剂；它们证实了整合素作为小分子靶点的普遍性；它们验证了α4β1作为哮喘治疗靶点的有效性。
Integrin alpha 4 beta 1 mediates leukocyte recruitment, activation, mediator release, and apoptosis inhibition, and it plays a central role in inflammatory pathophysiology. High-affinity, selective inhibitors of alpha 4 beta 1, based on the Leu-Asp-Val (LDV) sequence from the alternatively spliced connecting segment-1 (CS-1) peptide of cellular fibronectin, are described that employ a novel N-terminal peptide "cap" strategy. One inhibitor, BIO-1211, was similar to 10(6)-fold more potent than the starting peptide and exhibited tight-binding properties (k(off) = 1.4 x 10(-4) s(-1), K-D = 70 pM, a remarkable finding for a noncovalent, small-molecule inhibitor of a protein receptor. BIO-1211 was also 200-fold selective for the activated form of alpha 4 beta 1, and it stimulated expression of ligand-induced epitopes on the integrin beta 1 subunit, a property consistent with occupancy of the receptor's ligand-binding site. Pretreatment of allergic sheep with a 3-mg nebulized dose of BIO-1211 inhibited early and late airway responses following antigen challenge and prevented development of nonspecific airway hyperresponsiveness to carbachol. These results show that highly selective and potent small-molecule antagonists can be identified to integrins with primary specificity for peptide domains other than Arg-Gly-Asp (RGD); they confirm the generality of integrins as small molecule targets; and they validate alpha 4 beta 1 as a therapeutic target for asthma.