Synthesis and structure-activity relationship studies of marine-derived antimicrobial peptides and small cyclic peptidomimetics

Abstract

Effective antimicrobial drugs are the very core of modern medicine enabling successful prevention and treatment of infectious diseases. However, systemic misuse and overuse of antibiotics in human medicine, as well as in animal husbandry have led to widespread antibiotic-resistance, rendering many of these drugs ineffective. Therefore, there is an urgent need for new treatment options to conventional antibiotics. Antimicrobial peptides, also known as host defense peptides, are one such option. These compounds are an important part of the innate immune system of different organisms and they are generally characterised by being short, structurally diverse, positively charged and amphipathic in nature. However, their toxicity to host cells, along with their often moderate antimicrobial activity, pose a major obstacle for their development as antibiotics. To effectively address this challenge, we need to better understand the structure-activity relationship of these compounds. In the present work we investigated how different structural modifications affect antimicrobial and haemolytic properties of various marine-derived short antimicrobial peptides and cyclic peptidomimetics. We used three different peptide scaffolds: firstly, a 12-residue loop region of the marine antimicrobial peptide Turgencin A, secondly, a previously reported lead peptide (P6) derived from the heavy chain of the marine peptide EeCentrocin 1, and finally, a tetrapeptide scaffold containing non-canonical amino acid. We have shown that antimicrobial and haemolytic properties of Turgencin A and EeCentrocin 1 analogues can be fine-tuned by incorporating bulky, hydrophobic amino acids in the native sequence, by lysine to arginine substitution, and N-terminal acylation. For much smaller, tetrapeptide scaffold our study revealed that changes in amphipathicity and stereochemistry could be used to decrease the mammalian cell toxicity, while not significantly affecting potency of tetrapeptide analogues. In summary, our findings show that structural modifications performed in the present work could serve as a viable strategy for the development of potent, non-haemolytic antimicrobial agents, that could help address the growing problem of antibiotic resistance.