Optimization of sequence and chiral content enhances therapeutic potential of tilapia piscidin peptides

• Published in: European journal of medicinal chemistry Vol. 265; p. 116083
• Main Authors: Hsu, Po-Hsien, Hazam, Prakash Kishore, Huang, Yi-Ping, Yeh, Jih-Chao, Chen, Yun-Ru, Li, Chao-Chin, Chang, Chi-Fon, Liou, Je-Wen, Chen, Jyh-Yih
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.02.2024; Elsevier
• Subjects: Amino Acid Sequence; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Anti-Infective Agents; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial peptide; Chemistry, Medicinal; Heterochiral; Humans; Life Sciences & Biomedicine; Mice; Microbial Sensitivity Tests; Multidrug-resistant (MDR); NDM-1 K. pneumoniae; Pharmacology & Pharmacy; Science & Technology; Tilapia; Tilapia piscidin; Heterochiral; Multidrug-resistant (MDR); NDM-1 K. pneumoniae; Tilapia piscidin; Antimicrobial peptide; ANTIBIOTICS; D-AMINO-ACID; STABILITY; MODEL
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.116083

Because antimicrobial peptides (AMPs) often exhibit broad-spectrum bactericidal potency, we sought to develop peptide-based antimicrobials for potential clinical use against drug-resistant pathogens. To accomplish this goal, we first optimized the amino acid sequence of a broad-spectrum AMP known as Tilapia Piscidin 4 (TP4). Then, we used the optimized sequence to create a pair of heterochiral variants (TP4-α and TP4-β) with different percentages of D-enantiomers, as poly-L peptides often exhibit poor pharmacokinetic profiles. The conformations of the peptide pair exhibited inverted chirality according to CD and NMR spectroscopic analyses. Both heterochiral peptides displayed enhanced stability and low hemolysis activities. Irrespective of their different d-enantiomer contents, both heterochiral peptides exhibited bactericidal activities in the presence of human serum or physiological enzymes. However, the peptide with higher d-amino acid content (TP4-β) caused better bacterial clearance when tested in mice infected with NDM-1 K. pneumoniae. In addition, we observed a relatively higher hydrogen bonding affinity in a simulation of the interaction between TP4-β and a model bacterial membrane. In sum, our results demonstrate that the current design strategy may be applicable for development of new molecules with enhanced stability and in vivo antimicrobial activity. [Display omitted] •Antimicrobial peptide Tilapia Piscidin 4 displays low stability and high toxicity.•TP4 was modified by sequence optimization and selective chirality inversion.•The modifications lowered hemolysis and enhanced physiological stability.•Peptides with increased d-amino acid content displayed improved in vivo activity.