一种新型伤口愈合肽的设计及其在糖尿病足治疗中的应用研究

The wound in diabetic foot patients is easy to occur, difficult to treat and easy to recur due to the bacterial infection and out of control of wound healing process. Because the pathogenesis of diabetic foot is multifaceted, the development of corresponding therapeutic drugs becomes relatively difficult. In this project, based on our previous studies, we designed a novel type of hybrid peptides with antimicrobial activity and wound healing activity by connecting the neuropeptide SP and RGD using the multi-target drug design strategy, which can mimic the antimicrobial peptides with multiple functions secreted from skin. The ideal wound healing peptides with multiple functions to treat the diabetic foot with ulcer and bacterial infection are obtained by balancing the antimicrobial activity, agonistic activity to integrin and NK1 receptor. In a short, we hope to obtain effective lead compounds to treat diabetic foot through this project, and simultaneously explore the development of novel wound healing peptides with multi-targets and multiple functions.

糖尿病足患者由于伤口愈合环节失控，加之细菌感染导致皮肤易损伤、难治疗以及易复发。糖尿病足发病机理复杂，导致相应的治疗药物研发相对困难。本项目通过模仿皮肤抗菌肽的多功能特性，基于前期的工作基础，利用多靶点药物设计策略，将RGD多肽分子与神经肽SP偶联合成一类新型的具有抗菌活性和伤口愈合活性的杂合肽。通过结构优化平衡这类杂合肽药物的抗菌活性、整合素受体激动活性和NK1受体激动活性，最终筛选出理想的多功能伤口愈合肽，用于皮肤溃疡并伴有感染的糖尿病足的治疗。通过本项目的研究，我们希望能够获得治疗糖尿病足的高效先导化合物，同时也为发展具有多靶点和多功能的新型伤口愈合肽药物进行探索。

本项目以发展伤口治疗药物为目标，以具有多功能活性的神经肽为模板，利用嵌合肽策略和结构修饰策略，设计并合成了具有抗菌活性和伤口愈合活性的多肽药物。通过体外和体内活性的研究，我们从200多个类似物中筛选出了具有潜在临床应用价值的先导化合物，可以用于普通伤口、感染伤口以及病理状态下伤口的治疗。另外，本项目通过构效关系研究发现疏水性是影响抗菌肽抗菌选择性的一个非常重要的结构参数：在一定程度上，抗菌肽随着疏水性的增强对金黄色葡萄球菌的抗菌活性增加，而随着疏水性的降低对铜绿假单胞菌的抗菌活性增加。此外，我们还发展了一类低阳离子性的抗菌肽，能够高效抑制黑色素瘤的生长。总之，本项目为发展新型的多功能促伤口愈合药物提供了一种新的设计思路以及理论支持。