Tailoring of a membrane-active peptide with dual biological activities

患有癌症和多重耐药感染的人数正在稳步增加，因此这两种疾病已经被视为当前和未来的主要死亡原因。抗菌肽（Antimicrobial Peptides，AMP）是先天免疫系统的一部分，具有结构多样性，能迅速杀灭入侵的微生物。由于它们与传统抗生素相比的替代机制，它们被视为对抗感染的有希望的竞争者。此外，现在有大量的证据表明阳离子抗菌肽具有双重活性，既作为抗菌肽又作为抗癌肽。近年来，研究表明它们具有抑制癌细胞增殖的作用，因此，开发它们作为保护人类健康的新型生物制剂引起了人们极大的兴趣。近年来，我们对细胞穿透肽（CPP）进行了研究，它也属于这些阳离子膜活性肽，并且与它们在结构上相关。在以前的工作中，我们已经证明了CPP sC 18可以以选择性靶向癌细胞的方式进行调节和修饰。此外，sC 18的其他变体显示出有效的抗菌活性，同时保留了显著的抗癌作用。在这个项目中，我们的目标是针对两个观察到的活性谱，抗菌和抗癌，定制sC 18。因此，我们将生成许多不同的关键结构，探索肽序列内疏水/亲水比例的作用，以及限制肽骨架的影响。目的是（i）揭示其活性的分子基础，（ii）消除脱靶效应，以及（iii）提高在人血清中的稳定性。我们将测试这些肽的抗癌和抗菌活性机制、药物递送能力、抗生物膜形成和对细胞内病原体的作用。基于我们的结果，我们将确定理想的sC 18序列值得追求的未来前景作为新的药物对人类恶性肿瘤。

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.