背景:Sortilin1(SORT1)是一种广泛表达的转运蛋白,参与分选或清除蛋白质,在病理上与组织纤维化和钙化有关。靶向SORT1可能在控制或逆转心血管纤维化和/或钙化方面具有潜在的临床功效。因此,这项研究使用已知的nutra/药物评估了人类SORT1的蛋白质-蛋白质网络及其靶向性。
方法:使用String数据库鉴定了人类SORT1的网络蛋白,使用Chimera软件(Chimera-1.17.3-mac64)分析了该网络的蛋白质-蛋白质相互作用的亲和力。评估SORT1的组织特异性表达谱,并评估其在不同细胞类型中的富集,包括免疫细胞。使用AutoDockVina筛选了内部小分子和目前使用的心血管疾病治疗剂的文库,以评估人SORT1的靶向性。估计小分子的浓度亲和力(CA)比率以评估靶向SORT1的临床可行性。
结果:IGF2R,NTRK2、GRN和GGA1被鉴定为SORT1的高亲和力相互作用网络。在这些高亲和力相互作用中,IGF2R和GRN可以被认为是调节组织纤维化或微钙化过程的相关网络,因为它们对T细胞活化的影响。炎症,伤口修复,和组织重塑过程。组织细胞类型富集表明SORT1在脂肪细胞中主要表达,专门的上皮细胞,单核细胞,心肌细胞,和甲状腺腺细胞.人SORT1的结合袋分析显示了12个潜在的药物相互作用位点,具有不同的结合得分(0.86至5.83)和相互作用概率(0.004至0.304)。观察到五个药物相互作用位点在所评估的小分子的治疗可行浓度下是可靶向的。Empagliflozin,与已建立的SORT1抑制剂相比,西格列汀和番茄红素显示出优异的亲和力和CA比。
结论:IGF2R和GRN是SORT1的相关网络,调节组织纤维化或微钙化过程。SORT1可以使用目前批准的小分子疗法(依帕格列净和西格列汀)或广泛使用的营养品(番茄红素)靶向,应在随机临床试验中进行评估,以评估其减少心脏/血管微钙化过程的功效。
BACKGROUND: Sortilin1 (SORT1) is a ubiquitously expressed transporter involved in sorting or clearing proteins and is pathologically linked to tissue fibrosis and calcification. Targeting SORT1 may have potential clinical efficacy in controlling or reversing cardiovascular fibrosis and/or calcification. Hence, this study assessed the protein-protein network of human SORT1 and its targetability using known nutra-/pharmaceuticals.
METHODS: Network proteins of human SORT1 were identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software (Chimera-1.17.3-mac64). The tissue-specific expression profile of SORT1 was evaluated and assessed for enrichment in different cell types, including immune cells. A library of in-house small molecules and currently used therapeutics for cardiovascular diseases were screened using AutoDock Vina to assess the targetability of human SORT1. The concentration affinity (CA) ratio of the small molecules was estimated to assess the clinical feasibility of targeting SORT1.
RESULTS: IGF2R, NTRK2, GRN and GGA1 were identified as high-affinity interaction networks of SORT1. Of these high-affinity interactions, IGF2R and GRN can be considered relevant networks in regulating tissue fibrosis or the microcalcification process due to their influence on T-cell activation, inflammation, wound repair, and the tissue remodelling process. The tissue cell-type enrichment indicated major expression of SORT1 in adipocytes, specialised epithelial cells, monocytes, cardiomyocytes, and thyroid glandular cells. The binding pocket analysis of human SORT1 showed twelve potential drug interaction sites with varying binding scores (0.86 to 5.83) and probability of interaction (0.004 to 0.304). Five of the drug interaction sites were observed to be targetable at the therapeutically feasible concentration of the small molecules evaluated. Empagliflozin, sitagliptin and lycopene showed a superior affinity and CA ratio compared to established inhibitors of SORT1.
CONCLUSIONS: IGF2R and GRN are relevant networks of SORT1, regulating tissue fibrosis or the microcalcification process. SORT1 can be targeted using currently approved small-molecule therapeutics (empagliflozin and sitagliptin) or widely used nutraceuticals (lycopene), which should be evaluated in a randomised clinical trial to assess their efficacy in reducing the cardiac/vascular microcalcification process.