Gattringer Jasmin, Hasinger Simon, Weidmann Agnes, Walczewska-Szewc Katarzyna, Jadhav Kirtikumar B, Zrzavy Tobias, Steinmaurer Anja, Baeten Paulien, Perisic Monika, Cochrane Wilson, Muttenthaler Markus, Broux Bieke, Gotthardt Dagmar, Rosengren K Johan, Gruber Christian W, Hellinger Roland
Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
Institute of Physics, Faculty of Physics, Astronomy and Informatics, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland.
J Med Chem. 2025 Aug 28;68(16):17202-17220. doi: 10.1021/acs.jmedchem.5c00677. Epub 2025 Aug 12.
Lymphocyte migration plays a crucial role in the progression of autoimmune and inflammatory diseases, and the inhibition of autoreactive immune cells is an attractive therapeutic strategy. Pepitem is an endogenous modulator of lymphocyte migration. In this study, we implemented a structural scaffold matching approach to engineer of stabilized pepitem-based probes. Prioritizing the native helix-loop-helix structure of pepitem, protein structure databases were mined to identify the structurally closest peptide scaffold. Leveraging this strategy, we developed VhTI-pep 2, inhibiting CD3 T-lymphocyte migration in vitro with a comparable potency (EC = 10.6 ± 16.5 nM) to pepitem (EC = 6.0 ± 6.4 nM). Its potency was further extended to T-cell subsets derived from multiple sclerosis patients and highly disease-driving memory and Th1 cell populations. Our approach will guide the design of stabilized peptide probes and future therapeutics, overcoming the challenges associated with flexible and linear peptides.
淋巴细胞迁移在自身免疫性疾病和炎症性疾病的进展中起着关键作用，抑制自身反应性免疫细胞是一种有吸引力的治疗策略。肽素是淋巴细胞迁移的内源性调节剂。在本研究中，我们采用了结构支架匹配方法来设计基于肽素的稳定探针。优先考虑肽素的天然螺旋-环-螺旋结构，挖掘蛋白质结构数据库以识别结构上最接近的肽支架。利用这一策略，我们开发了VhTI-肽2，其在体外抑制CD3 T淋巴细胞迁移的效力（EC = 10.6 ± 16.5 nM）与肽素（EC = 6.0 ± 6.4 nM）相当。其效力进一步扩展到来自多发性硬化症患者的T细胞亚群以及高度驱动疾病的记忆和Th1细胞群体。我们的方法将指导稳定肽探针和未来治疗药物的设计，克服与柔性线性肽相关的挑战。
