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，以至于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(AMPs)是天然免疫系统的一部分，结构多样，能迅速灭活入侵的微生物。由于它们与传统抗生素相比具有替代机制，它们被视为抗击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，既是抗菌肽，又是抗癌肽。近年来，它们被证明能够有效地抑制癌细胞的增殖，因此它们作为一种新型的生物制剂来保护人类健康引起了人们的极大兴趣。近年来，我们致力于细胞穿透肽(CPP)的研究，它也属于阳离子膜活性多肽的一类，并且与它们的结构相关。在以前的工作中，我们已经证明了CPP sC18可以通过选择性靶向癌细胞的方式进行调整和修饰。此外，sC18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光谱--抗菌和抗癌--量身定做sC18。因此，我们将生成一些不同的关键结构，探索疏水/亲水比在多肽序列中的作用，以及限制多肽骨架的影响。目的是(I)揭示其活性的分子基础，(Ii)消除靶外效应，(Iii)提高人血清中的稳定性。我们将测试这些多肽的抗癌和抗菌活性机制、药物输送能力、抗生物被膜形成和对细胞内病原体的影响。根据我们的结果，我们将确定理想的sC18序列，为未来作为抗人类恶性肿瘤新药的前景而努力。

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.