Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.
Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, 40126 Bologna, Italy.
Int J Mol Sci. 2023 May 31;24(11):9588. doi: 10.3390/ijms24119588.
Integrin receptors mediate cell-cell interactions via the recognition of cell-adhesion glycoproteins, as well as via the interactions of cells with proteins of the extracellular matrix, and upon activation they transduce signals bi-directionally across the cell membrane. In the case of injury, infection, or inflammation, integrins of β and α families participate in the recruitment of leukocytes, a multi-step process initiated by the capturing of rolling leukocytes and terminated by their extravasation. In particular, αβ integrin is deeply involved in leukocyte firm adhesion preceding extravasation. Besides its well-known role in inflammatory diseases, αβ integrin is also involved in cancer, being expressed in various tumors and showing an important role in cancer formation and spreading. Hence, targeting this integrin represents an opportunity for the treatment of inflammatory disorders, some autoimmune diseases, and cancer. In this context, taking inspiration from the recognition motives of αβ integrin with its natural ligands FN and VCAM-1, we designed minimalist α/β hybrid peptide ligands, with our approach being associated with a retro strategy. These modifications are expected to improve the compounds' stability and bioavailability. As it turned out, some of the ligands were found to be antagonists, being able to inhibit the adhesion of integrin-expressing cells to plates coated with the natural ligands without inducing any conformational switch and any activation of intracellular signaling pathways. An original model structure of the receptor was generated using protein-protein docking to evaluate the bioactive conformations of the antagonists via molecular docking. Since the experimental structure of αβ integrin is still unknown, the simulations might also shed light on the interactions between the receptor and its native protein ligands.
整合素受体通过识别细胞黏附糖蛋白，以及细胞与细胞外基质蛋白的相互作用，介导细胞-细胞相互作用，并且在激活后，它们在细胞膜两侧双向传递信号。在受伤、感染或炎症的情况下，β和α家族的整合素参与白细胞的募集，这是一个由滚动白细胞捕获启动、并由其渗出终止的多步骤过程。特别是，αβ整合素深度参与白细胞的牢固黏附，随后是渗出。除了在炎症性疾病中众所周知的作用外，αβ整合素还参与癌症，在各种肿瘤中表达，并在癌症的形成和扩散中发挥重要作用。因此，靶向该整合素为治疗炎症性疾病、一些自身免疫性疾病和癌症提供了机会。在这种情况下，我们从αβ整合素与其天然配体 FN 和 VCAM-1 的识别基序中获得灵感，设计了极简的α/β混合肽配体，我们的方法与回溯策略相关联。这些修饰预计会提高化合物的稳定性和生物利用度。事实证明，一些配体被发现是拮抗剂，能够抑制整合素表达细胞与天然配体涂覆的平板的黏附，而不会诱导任何构象转变和任何细胞内信号通路的激活。使用蛋白-蛋白对接生成受体的原始模型结构，通过分子对接评估拮抗剂的生物活性构象。由于αβ整合素的实验结构仍然未知，模拟也可能揭示受体与其天然蛋白配体之间的相互作用。
