Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Faculty of Medicine, Université libre de Bruxelles, Brussels, Belgium.
Faculty of Chemistry, University of Warsaw, Warsaw, Poland.
Front Endocrinol (Lausanne). 2021 Nov 18;12:711906. doi: 10.3389/fendo.2021.711906. eCollection 2021.
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two neuropeptides that contribute to the regulation of intestinal motility and secretion, exocrine and endocrine secretions, and homeostasis of the immune system. Their biological effects are mediated by three receptors named VPAC1, VPAC2 and PAC1 that belong to class B GPCRs. VIP and PACAP receptors have been identified as potential therapeutic targets for the treatment of chronic inflammation, neurodegenerative diseases and cancer. However, pharmacological use of endogenous ligands for these receptors is limited by their lack of specificity (PACAP binds with high affinity to VPAC1, VPAC2 and PAC1 receptors while VIP recognizes both VPAC1 and VPAC2 receptors), their poor oral bioavailability (VIP and PACAP are 27- to 38-amino acid peptides) and their short half-life. Therefore, the development of non-peptidic small molecules or specific stabilized peptidic ligands is of high interest. Structural similarities between VIP and PACAP receptors are major causes of difficulties in the design of efficient and selective compounds that could be used as therapeutics. In this study we performed structure-based virtual screening against the subset of the ZINC15 drug library. This drug repositioning screen provided new applications for a known drug: ticagrelor, a P2Y12 purinergic receptor antagonist. Ticagrelor inhibits both VPAC1 and VPAC2 receptors which was confirmed in VIP-binding and calcium mobilization assays. A following analysis of detailed ticagrelor binding modes to all three VIP and PACAP receptors with molecular dynamics revealed its allosteric mechanism of action. Using a validated homology model of inactive VPAC1 and a recently released cryo-EM structure of active VPAC1 we described how ticagrelor could block conformational changes in the region of 'tyrosine toggle switch' required for the receptor activation. We also discuss possible modifications of ticagrelor comparing other P2Y12 antagonist - cangrelor, closely related to ticagrelor but not active for VPAC1/VPAC2. This comparison with inactive cangrelor could lead to further improvement of the ticagrelor activity and selectivity for VIP and PACAP receptor sub-types.
血管活性肠肽（VIP）和垂体腺苷酸环化酶激活肽（PACAP）是两种神经肽，它们有助于调节肠道运动和分泌、外分泌和内分泌分泌以及免疫系统的稳态。它们的生物学效应是由三种受体介导的，这三种受体分别命名为 VPAC1、VPAC2 和 PAC1，它们属于 B 类 GPCR 家族。VIP 和 PACAP 受体已被确定为治疗慢性炎症、神经退行性疾病和癌症的潜在治疗靶点。然而，内源性配体对这些受体的药理学应用受到限制，原因是它们缺乏特异性（PACAP 与 VPAC1、VPAC2 和 PAC1 受体具有高亲和力，而 VIP 则识别 VPAC1 和 VPAC2 受体）、口服生物利用度差（VIP 和 PACAP 是 27 到 38 个氨基酸的肽）和半衰期短。因此，开发非肽小分子或特定稳定的肽配体具有很高的兴趣。VIP 和 PACAP 受体之间的结构相似性是设计有效和选择性化合物作为治疗药物的主要困难原因。在这项研究中，我们针对 ZINC15 药物库的子集进行了基于结构的虚拟筛选。这种药物重新定位筛选为一种已知药物提供了新的应用：替格瑞洛，一种 P2Y12 嘌呤能受体拮抗剂。替格瑞洛抑制 VPAC1 和 VPAC2 两种受体，这在 VIP 结合和钙动员测定中得到了证实。随后对替格瑞洛与所有三种 VIP 和 PACAP 受体的详细结合模式进行的分子动力学分析揭示了其变构作用机制。使用 VPAC1 的已验证的同源无活性模型和最近发布的活性 VPAC1 的冷冻电镜结构，我们描述了替格瑞洛如何阻断受体激活所需的“酪氨酸Toggle 开关”区域的构象变化。我们还讨论了替格瑞洛的可能修饰，比较了与其密切相关但对 VPAC1/VPAC2 无活性的另一种 P2Y12 拮抗剂坎格雷洛。与无活性坎格雷洛的这种比较可能会进一步提高替格瑞洛对 VIP 和 PACAP 受体亚型的活性和选择性。
