Tailoring of a membrane-active peptide with dual biological activities

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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.