Hydrophobic-hydrophilic Alternation: An effective Pattern to de novo Designed Antimicrobial Peptides

The antimicrobial peptide (AMP) is a class of molecules that are active against a variety of microorganisms, from bacterial and cancer cells to fungi. Most AMPs are natural products, as part of an organism's own defense system against harmful microbes. However, the growing prevalence of drug resistance has forced researchers to design more promising engineered antimicrobial agents. Inspired by the amphiphilic detergents, the hydrophobic-hydrophilic alternation pattern was considered to be a simple but effective way to de novo design AMPs. In this model, hydrophobic amino acids (leucine, isoleucine etc.) and hydrophilic amino acids (arginine, lysine etc.) were arranged in an alternating way in the peptide sequence. The majority of this type of peptides have a clear hydrophilic-hydrophobic interface, which allows the molecules to have good solubility in both water and organic solvents. When they come into contact with hydrophobic membranes, many peptides undergo a conformational transformation, facilitating themself to insert into the cellular envelope. Moreover, positive-charged peptide amphiphiles tended to have an affinity with negatively-charged membrane interfaces and further led to envelope damage and cell death. Herein, several typical design patterns have been reviewed. Though varying in amino acid sequence, they all basically follow the rule of alternating arrangement of hydrophilic and hydrophobic residues. Based on that, researchers synthesized some lead compounds with favorable antimicrobial activities and preliminarily investigated their possible mode of action. Besides membrane disruption, these AMPs are proven to kill microbes in multiple mechanisms. These results deepened our understanding of AMPs' design and provided a theoretical basis for constructing peptide candidates with better biocompatibility and therapeutic potential.