美国哈佛医学院Timothy A. Springer等研究人员合作揭示创造封闭稳定的整合素抑制剂的一种通用化学原理。这一研究成果发表在2022年9月15日出版的国际学术期刊《细胞》上。

研究人员表明，失败的小分子整合素αIIbβ3和α4β1抑制剂稳定了高亲和力的构象。此外，研究人员发现了存在于多种αIIbβ3拮抗剂中的一个简单的化学特征，它能使整合素稳定在其弯曲封闭的构象中。闭合抑制剂含有一个极性氮原子，通过氢键稳定一个水分子，该水分子介于一个丝氨酸残基和金属离子依赖的粘附位点（MIDAS）之间。这个水分子的排出是过渡到开放构象的一个必要条件。金属配位的这种变化对整合素来说是普遍的，这表明药物设计原则对整合素家族有广泛的适用性，这一点已在远缘整合素α4β1中得到验证。

据介绍，整合素是经过验证的药物靶点，有六种被批准的治疗方法。然而，三种整合素的小分子抑制剂在慢性适应症的后期临床试验中失败。这种不利的结果可能部分是由部分激动作用造成的，即高亲和力、扩展开放的整合素构象的稳定化。

附：英文原文

Title: A general chemical principle for creating closure-stabilizing integrin inhibitors

Author: Fu-Yang Lin, Jing Li, Yonghua Xie, Jianghai Zhu, Thi Thu Huong Nguyen, Yonghui Zhang, Jieqing Zhu, Timothy A. Springer

Issue&Volume: 2022/09/15

Abstract: Integrins are validated drug targets with six approved therapeutics. However, small-moleculeinhibitors to three integrins failed in late-stage clinical trials for chronic indications.Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilizationof the high-affinity, extended-open integrin conformation. Here, we show that thefailed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinityconformation. Furthermore, we discovered a simple chemical feature present in multipleαIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closinginhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a watermolecule that intervenes between a serine residue and the metal in the metal-ion-dependentadhesion site (MIDAS). Expulsion of this water is a requisite for transition to theopen conformation. This change in metal coordination is general to integrins, suggestingbroad applicability of the drug-design principle to the integrin family, as validatedwith a distantly related integrin, α4β1.

DOI: 10.1016/j.cell.2022.08.008

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00995-3