De Novo Design of Triblock Amphiphilic Short Antimicrobial Peptides

Abstract

Antimicrobial peptides (AMPs) exhibit excellent antibacterial capability, and their antibacterial mechanism hardly causes bacterial resistance. Past work on designing AMPs has focused on synthesizing sequences similar to those of natural AMPs. The design and synthesis of highly selective AMPs are important research topics. Triblock amphiphilic peptides (K n F m K n ) possess different amino acid sequences and conformations compared with natural AMPs. K n F m K n remain highly active against both Gram-negative and Gram-positive bacteria. The results proved that the newly designed AMPs can focus on the two main elements of the antibacterial mechanism of natural AMPs: the positive charge and hydrophobic amino acids. Suitable aggregates of lysine and long hydrophobic chain length effectively kill bacteria. Minimum inhibitory concentration and hemolysis results showed that these synthetic AMPs exhibit high selectivity against bacteria. The animal infection model experiment showed that these triblock peptides exhibited evident therapeutic effects on bacterial infection. Therefore, the triblock amphiphilic antibacterial peptides exhibit potential applications in the clinical treatment of bacterial infection.

Therapeutic Effects of Synthetic Triblock Amphiphilic Short Antimicrobial Peptides on Human Lung Adenocarcinoma

“…The four peptides used in this study, namely, K 2 F 6 K 2 , K 3 F 6 K 3 , K 4 F 6 K 4 , and K 4 F 8 K 4 , were the same batch as those previously described. Thus, we had already confirmed their antibacterial effects both in vitro and in vivo [ 24 ]. Their basic properties are displayed in Table 1 .…”

“…Previously, we designed and synthesized a series of novel triblock amphiphilic short AMPs (K n F m K n : K 2 F 6 K 2 , K 3 F 6 K 3 , K 4 F 6 K 4 , and K 4 F 8 K 4 ) which were demonstrated to exhibit evident therapeutic effects on bacterial infection, both in vitro and in vivo [ 24 ]. We extended our investigations to the antitumor ability of these analogues against the human lung cancer cell line A549 and its underlying mechanisms.…”

Disclosure of a Promising Lead to Tackle Complicated Skin and Skin Structure Infections: Antimicrobial and Antibiofilm Actions of Peptide PP4-3.1

“…Rational design, along with chemical synthesis, offers a multiplicity of peptide-based constructs with no match in Nature, enabling a fine tuning of their pharmacodynamic and pharmacokinetic properties, thereby improving their fitness to reach the clinics [40][41][42]. De novo design has been delivering very promising HDP in the past couple of years such as, e.g., short amphiphilic peptides possessing the general structure K n F m K n [43] and activity against antibiotic-susceptible strains of E. coli and S. aureus (2 ≤ MIC ≤ 32 mg/mL), or a structure based on IIKK repeat units conferring selective activity against antibioticsusceptible E. coli (8 ≤ MIC ≤ 16 mg/mL) due to the ability to specifically interact with the outer membrane of this bacterium [44]. Computer-aided rational design of HDP is widening the chemical space around antimicrobial peptides [45], which, together with growing knowledge on specific features of bacterial cell surfaces, allows the tailoring of biomimetic peptides able to, e.g., overcome the extracellular polysaccharide capsule of Klebsiella pneumoniae [46] or specifically interact with the mycolic acid-rich envelope of Mycobacterium tuberculosis, killing this bacterium [47].…”