Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma.
Rational design of potent and selective VLA-4 inhibitors and their utility in the treatment of asthma.
复制标题
有效和选择性 VLA-4 抑制剂的合理设计及其在哮喘治疗中的应用。
DOI：
--
复制
发表时间：
2004
影响因子：
3.4
通讯作者：
D. Scott
中科院分区：
文献类型：
--
作者：
Juswinder Singh;S. Adams;M. B. Carter;Hernan Cuervo;Wen;R. Lobb;R. Pepinsky;R. Petter;D. Scott
哮喘是一种慢性呼吸道炎症性疾病，是我们医疗保健系统的重大负担。针对这种疾病的根本原因的治疗需求高度未得到满足。细胞表面整合素VLA-4(非常晚的抗原-4；α4beta1；CD49d/CD29)在白细胞向炎症部位的运输中发挥重要作用，是开发治疗哮喘的新型抗炎药物的一个令人兴奋的靶点。在这里，我们回顾了我们的努力，使用合理的设计来确定有效的，选择性的VLA-4抑制剂。我们描述了通过在四肽VLA-4结合基序4-((N‘-2-methylphenyl)uriedo)phenylacetyl-Leu-Asp-Val-Pro上添加一个新的N端有机帽来发现一系列有效的VLA-4抑制剂，并使用3D-QSAR对它们的构效关系进行了合理化。此外，我们还展示了我们基于GPIIb/IIIa整合素拮抗剂领域的“模板跳跃”的合理的拟肽设计策略，以及一种新的虚拟筛选策略。已经开发出两个系列，一个对激活的VLA-4具有比受体非激活状态高的选择性，另一个非选择性地抑制激活和非激活的VLA-4。与其他整合素家族成员相比，这两个系列对VLA-4具有高度的选择性。基于对绵羊哮喘模型的疗效，这些抑制剂在治疗哮喘方面显示出很好的前景，在羊哮喘模型中，它们既抑制对哮喘的早期和晚期反应，也抑制过敏反应。
Asthma, a chronic inflammatory disease of the airways, is a significant burden on our healthcare system. There is high unmet need for treatments directed towards the underlying causes of the disease. The cell surface integrin VLA-4 (very late antigen-4; alpha4beta1; CD49d/CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti-inflammatory drugs for the treatment of asthma. Here, we review our efforts to use rational design to identify potent, selective inhibitors of VLA-4. We describe the discovery of a series of potent VLA-4 inhibitors through the addition of a novel N-terminal organic cap to a tetrapeptide VLA-4 binding motif 4-((N'-2-methylphenyl)uriedo)phenylacetyl-Leu-Asp-Val-Pro ; Kd = 70 pM), and rationalize their structure-activity relationships using 3D-QSAR. Also, we show our rational peptidomimetic design strategy using "template hopping" from the gpIIb/IIIa integrin antagonist field, and also a novel virtual screening strategy. Two series have been developed, one that has high selectivity for the activated over the non-activated state of the receptor, and the other which is non-selective inhibiting both activated and non-activated VLA-4. Both series are highly selective for VLA-4 versus against other integrin family members. These inhibitors show promise in the treatment of asthma, based upon efficacy in a sheep model of asthma, where they inhibit both the early and late-phase responses to asthma and also block hypersensitivity.