Discovery, Optimization, and Clinical Application of Natural Antimicrobial Peptides

Abstract

Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and anticancer activities. During the last 30 years, technological advances have boosted the research on antimicrobial peptides, which have also attracted great interest as an alternative to tackling the antimicrobial resistance scenario mainly provoked by some bacterial and fungal pathogens. However, the introduction of natural AMPs in clinical trials faces challenges such as proteolytic digestion, short half-lives, and cytotoxicity upon systemic and oral application. Therefore, some strategies have been implemented to improve the properties of AMPs aiming to be used as effective therapeutic agents. In the present review, we summarize the discovery path of AMPs, focusing on preclinical development, recent advances in chemical optimization and peptide delivery systems, and their introduction into the market.

Site-Specific Isopeptide Bond Formation: A Powerful Tool for the Generation of Potent and Nontoxic Antimicrobial Peptides

“… 25 − 27 Rational design approaches have been used to generate synthetic analogs of antimicrobial peptides, reducing the limitations and increasing advantages. 1 , 11 However, several AMPs have failed in phase II and III testing 28 because AMPs are vulnerable to proteolysis and have toxicity associated with mammalian membrane lysis. 29 We have shown a new strategy that improved the antimicrobial peptide analogs.…”

“…8 − 10 Several approaches were suggested to overcome these hurdles, such as incorporating unnatural amino acids, substituting l -proteinogenic amino acids with d -proteinogenic amino acids, N-terminal acetylation, C-terminal amidation, cylization, lipidation, and replacing amino acids. 11 − 16 A new approach to modulate AMPs uses an isopeptide bond replacement. 17 The isopeptide bond is an amide bond between the carboxyl group of one amino acid and the epsilon amino group of another amino acid.…”

Emerging Computational Approaches for Antimicrobial Peptide Discovery

“…Hence, the integration of OMICs approaches is more recommendable than the classical ones at the early stage of bioactive peptide discovery. However, bioassays-guided methods are still valid and complementary at advanced phases of the research [ 140 , 145 ].…”

Optimized peptide extraction method for analysis of antimicrobial peptide Kn2-7/dKn2-7 stability in human serum by LC–MS

“…Every year multidrug resistant microbes infect millions of people worldwide, with many dying of the infection [ 26 ]. As promising next generation antibiotics, AMPs are a potential alternative to conventional drugs, are suitable for topical therapeutic applications for treating multidrug resistant infections [ 27 ] and pose a lower risk of inducing drug resistance than traditional antimicrobials [ 28 ]. Peptides typically do not possess sufficient conformational stability that is essential for use of therapeutic candidates within biological environments [ 29 ]; thus, evaluation of peptide stability in serum is a necessary assay for the selection of appropriate leads in the process of AMP drug development.…”