Strategies employed in the design of antimicrobial peptides with enhanced proteolytic stability

Due to the alarming developing rate of multidrug-resistant bacterial pathogens, the development and modification of antimicrobial peptides (AMPs) are unprecedentedly active. Despite the fact that considerable efforts have been expended on the discovery and design strategies of AMPs, the clinical translation of peptide antibiotics remains inadequate. A large number of articles and reviews credited the limited success of AMPs to their poor stability in the biological environment, particularly their poor proteolytic stability. In the past forty years, various design strategies have been used to improve the proteolytic stability of AMPs, such as sequence modification, cyclization, peptidomimetics, and nanotechnology. Herein, we focus our discussion on the progress made in improving the proteolytic stability of AMPs and the principle, successes, and limitations of various anti-proteolytic design strategies. It is of prospective significance to extend current insights into the degradation-related inactivation of AMPs and also alleviate/overcome the problem.