Tailoring of a membrane-active peptide with dual biological activities

具有双重生物活性的膜活性肽的剪裁

• 批准号: 410897008
• 负责人: Professorin Dr. Ines Neundorf
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410897008?language=en
• 关键词: Tailoring; membrane; active; peptide; dual

The number of people suffering from cancer and multi-resistant infections is steadily increasing, such that both diseases are already seen as current and future major causes of death. Antimicrobial peptides (AMPs) are part of the innate immune system, structurally diverse and rapidly act to inactivate invading microorganisms. Owing to their alternative mechanisms compared to conventional antibiotics, they are seen as promising contenders in the fight against infections. Moreover, there is now an abundance of evidence that cationic antimicrobial peptides possess dual activity, both as antimicrobial and anticancer peptides. In recent years, it has been shown that they are effective at restraining cancer cell proliferation, and have consequently stimulated significant interest in their development as novel biologic agents to safeguard human health.Since several years, we work on cell-penetrating peptides (CPP), which also fall in the group of these cationic membrane-active peptides and are structurally related with them. In previous work we have demonstrated that the CPP sC18 can be tuned and modified in such a way that it selectively targets cancer cells. Moreover, other variants of sC18 showed effective antibacterial activity, while retaining a pronounced anticancer effect. Within this project we aim to tailor sC18 against the two observed activity spectra, antibacterial and anticancer. Therefore, we will generate a number of different key structures, explore the role of the hydrophobic/hydrophilic ratio within the peptide sequence, and the impact of constraining the peptide backbone. Aim is (i) to uncover the molecular basis of their activity, (ii) to eliminate off-target effects, and (iii) to improve stability in human serum. We will test the peptides for their anticancer and antibacterial activity mechanisms, drug delivery capability, anti-biofilm formation and effects against intracellular pathogens. Based on our results we will determine the ideal sC18 sequences worth to pursuit for the future prospect as novel agents against human malignancies.

患有癌症和多重耐药感染的人数正在稳步增加，因此这两种疾病已被视为当前和未来的主要死亡原因。抗菌肽 (AMP) 是先天免疫系统的一部分，结构多样，可快速灭活入侵的微生物。由于与传统抗生素相比，它们具有替代机制，因此被视为对抗感染的有希望的竞争者。此外，现在有大量证据表明阳离子抗菌肽具有抗菌肽和抗癌肽的双重活性。近年来，它们已被证明可以有效抑制癌细胞增殖，因此激发了人们对将其开发为维护人类健康的新型生物制剂的浓厚兴趣。多年来，我们致力于细胞穿透肽（CPP）的研究，它也属于这些阳离子膜活性肽，并且在结构上与它们相关。在之前的工作中，我们已经证明 CPP sC18 可以通过调整和修饰来选择性地靶向癌细胞。此外，sC18的其他变体表现出有效的抗菌活性，同时保留了显着的抗癌作用。在这个项目中，我们的目标是根据观察到的两种活性谱（抗菌和抗癌）定制 sC18。因此，我们将生成许多不同的关键结构，探索肽序列中疏水/亲水比的作用，以及限制肽主链的影响。目的是（i）揭示其活性的分子基础，（ii）消除脱靶效应，以及（iii）提高人血清中的稳定性。我们将测试这些肽的抗癌和抗菌活性机制、药物输送能力、抗生物膜形成以及对细胞内病原体的作用。根据我们的结果，我们将确定理想的 sC18 序列，作为对抗人类恶性肿瘤的新型药物，未来值得追求。