Discovery of novel histidine-derived lipo-amino acids: applied in the synthesis of ultra-short antimicrobial peptidomimetics having potent antimicrobial activity, salt resistance and protease stability.
Here we report for the first time the synthesis of Histidine (His) derived lipo-amino acids having pendant lipid tails at N(τ)- and N(π)-positions on imidazole group of His and applied it into synthesis of lipo-peptides. The attachment of His-derived lipo-amino acid into the very short inactive cationic peptides endows potent antimicrobial activity against Gram-positive and Gram-negative bacteria without hemolytic activity. Furthermore, our designed His-derived lipo-peptidomimetics (HDLPs) consisting of two or three residues displayed strong anti-MRSA activity and protease stability as well as retained potent antimicrobial activity under high salt concentration. Our results demonstrate that the novel lipo-amino acid is highly flexible to synthesize and carry out the extensive structure-activity relationship (SAR) on lipo-antimicrobial peptidomimetics and represents a unique amenable platform for modifying parameters important for antimicrobial activity. Through this study, we proved that the discovery of His-derived lipo-amino acid and the corresponding HDLPs are an excellent candidate as a lead compound for the development of novel antimicrobial agents.
Division of Magnetic Resonance, Korea Basic Science Institute, Ochang, Cheongwon, Chung-Buk 363-883, Republic of Korea.
Mija
M
Ahn
Ravichandran N
RN
Murugan
Binu
B
Jacob
Jae-Kyung
JK
Hyun
Chaejoon
C
Cheong
Eunha
E
Hwang
Hyo-Nam
HN
Park
Ji-Hyung
JH
Seo
G
G
Srinivasrao
Kyung S
KS
Lee
Song Yub
SY
Shin
Jeong Kyu
JK
Bang
D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D055808:Drug Discovery; D004355:Drug Stability; D006639:Histidine / Q000737:chemistry*; D008074:Lipoproteins / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000737:chemistry / Q000494:pharmacology; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000494:pharmacology*; D012492:Salts / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D008074:Lipoproteins; D057786:Peptidomimetics; D012492:Salts; D006639:Histidine; D010447:Peptide Hydrolases
Anti-MRSA activity; Antimicrobial peptidomimetics; Histidine-derived amino acid; Protease stability; Salt resistance