Abstract：
Uterine fibroid is the most common non-cancerous tumor with no satisfactory options for long-term pharmacological treatment. Fibroblast activation protein-α (FAP) is one of the critical enzymes that enhances the fibrosis in uterine fibroids. Through STITCH database mining, we found that dipeptidyl peptidase-4 inhibitors (DPP4i) have the potential to inhibit the activity of FAP. Both DPP4 and FAP belong to the dipeptidyl peptidase family and share a similar catalytic domain. Hence, ligands which have a binding affinity with DPP4 could also bind with FAP. Among the DPP4i, linagliptin exhibited the highest binding affinity (Dock score = -8.562 kcal/mol) with FAP. Our study uncovered that the differences in the S2 extensive-subsite residues between DPP4 and FAP could serve as a basis for designing selective inhibitors specifically targeting FAP. Furthermore, in a dynamic environment, linagliptin was able to destabilize the dimerization interface of FAP, resulting in potential inhibition of its biological activity. True to the in-silico results, linagliptin reduced the fibrotic process in estrogen and progesterone-induced fibrosis in rat uterus. Furthermore, linagliptin reduced the gene expression of transforming growth factor-β (TGF-β), a critical factor in collagen secretion and fibrotic process. Masson trichrome staining confirmed that the anti-fibrotic effects of linagliptin were due to its ability to reduce collagen deposition in rat uterus. Altogether, our research proposes that linagliptin has the potential to be repurposed for the treatment of uterine fibroids.
摘要：
子宫肌瘤是最常见的非癌性肿瘤，长期药物治疗没有令人满意的选择。成纤维细胞活化蛋白-α（FAP）是增强子宫肌瘤纤维化的关键酶之一。通过STITCH数据库挖掘,我们发现二肽基肽酶-4抑制剂(DPP4i)具有抑制FAP活性的潜力。DPP4和FAP都属于二肽基肽酶家族并且共享相似的催化结构域。因此，与DPP4具有结合亲和力的配体也可以与FAP结合。在DPP4i中，利格列汀与FAP的结合亲和力最高（Dock评分=-8.562kcal/mol）。我们的研究发现，DPP4和FAP之间S2广泛亚位点残基的差异可以作为设计特异性靶向FAP的选择性抑制剂的基础。此外，在动态环境中，利拉列汀能够破坏FAP的二聚化界面，导致其生物活性的潜在抑制。忠实于计算机结果，利格列汀可减少雌激素和孕激素诱导的大鼠子宫纤维化过程。此外，利格列汀降低转化生长因子-β（TGF-β）的基因表达，胶原蛋白分泌和纤维化过程中的一个关键因素。Masson三色染色证实，利格列汀的抗纤维化作用是由于其减少大鼠子宫中胶原蛋白沉积的能力。总之,我们的研究表明,利格列汀有可能用于子宫肌瘤的治疗.
