Improving Antimicrobial Peptides Translational Potential Through Peptidomimetics

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Background

Microbial infections represent one of the main threats to human health. It is estimated that multidrug resistant (MDR) microorganisms contribute to over 700,000 deaths annually worldwide, and it is expected to reach ~10 million by 2050. This scenario is even more alarming considering the drastic decrease in the discovery and development of effective anti-infective medicines since the 1980s. Currently, most antimicrobial therapies include monotherapies, in which the most effective agents are often used as a last resort for MDR infections treatment. Additionally, combination therapies have also been proposed for antimicrobial agents with different mechanisms of action and, although controversial, some positive outcomes have been reported.

As an alternative to the conventional antimicrobial therapies, the interest in antimicrobial peptides (AMPs) has greatly increased in the last decade. Naturally occurring AMPs have been identified from most living organisms, including animals, plants, bacteria and fungi. Moreover, numerous AMP design strategies have been developed over the years, aiming at overcoming some therapeutic limitations, including toxicity to the host. Among them, we can cite the physicochemical prorpeties guided design of AMP analogs, which mainly occur by key amino acid substitutions. Additionally, de novo and structure-guided strategies have also been used for short AMP design. Finally, considering the groundbreaking advances in bioinformatics, the computer-guided design of AMPs and
chemoinformatics has demonstrated a huge potential to identify physicochemical and structural determinants for a given biological activity, including antibacterial, antibiofilm and antifungal properties, with high selectivity.

As expected, all these design tools have contributed to generate potent AMP candidates that have been fully characterized functionally and structurally. Consequently, thousands of AMP sequences have been deposited on public databases and used as scaffolds for further AMP design studies. Nevertheless, it is worth noting the discrepancy of AMP sequences deposited on databases and those submitted to preclinical and clinical trials, thus indicating the limitations to translate this class of antimicrobial to the clinic. Among the main obstacles, we can cite AMP's low bioavailability, toxicity to the host, rapid renal clearance, divergence between in vitro and in vivo assays and synthesis cost. As a response to these challenges, small, peptide-like molecules called peptidomimetics have been designed to mimic AMPs and potentially possess better pharmacological properties.

In this context, this Research Topic aims to strengthen the pros and cons of using peptidomimetics strategies in the field of AMPs to improve the translational potential of this class of antimicrobials to the clinic. Therefore, this Research Topic highlights how AMPs can be successfully submitted to chemical modifications, including glycosylation, PEGylation, lipidation, stapling, chirality inversion, head-to-tail or head-to-side chain cyclization and peptide grafting into a constrained scaffold for generating peptide therapeutics, with a core focus on MDR infections treatment.

Keywords: AMPs, antimicrobial peptides, peptidomimetics

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