Antimicrobial activity of leucine‐substituted decoralin analogs with lower hemolytic activity

Abstract

Linear cationic α-helical antimicrobial peptides are promising chemotherapeutics. Most of them act by different mechanisms, making it difficult to microorganisms acquiring resistance. Decoralin is an example of antimicrobial peptide; it was described by Konno et al. and presented activity against microorganisms, but with pronounced hemolytic activity. We synthesized leucine-substituted decoralin analogs designed based on important physicochemical properties, which depend on the maintenance of the amphiphilic α-helical tendency of the native molecule. Peptides were synthesized, purified, and characterized, and the conformational studies were performed. The results indicated that the analogs presented both higher therapeutic indexes, but with antagonistic behavior. While [Leu] -Dec-NH analog showed similar activity against different microorganisms (c.a. 0.4-0.8 μmol L ), helical structuration, and some hemolytic activity, [Leu] -Dec-NH analog did not tend to helical structure and presented antimicrobial activities two orders higher than the other two peptides analyzed. On the other hand, this analog showed to be the less hemolytic (MHC value = 50.0 μmol L ). This approach provided insight for understanding the effects of the leucine substitution in the amphiphilic balance. They led to changes on the conformational tendency, which showed to be important for the mechanism of action and affecting antimicrobial and hemolytic activities. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Reprogramming biological peptides to combat infectious diseases

“…The helicity of the decoralin family did not correlate to activity, although the balance between the increased hydrophobicity and the insertion of positively charged residues on the hydrophilic face and on the interface of the helical structure generated highly active peptides. 41,42 The decoralin derivatives also inhibited the growth of MCF-7 human breast cancer cells 43 and Plasmodium sporozoites. 44 High-throughput peptide synthesis, by enabling the correlation of the most important biological descriptors with the biological activities of the peptides, 45 is another powerful tool for mutagenesis studies.…”

Natural and redesigned wasp venom peptides with selective antitumoral activity

“…Antimicrobial peptides (AMPs) are produced by the innate immune system of virtually every organism on Earth. These agents represent promising anticancer candidates since, in addition to their activity vs bacteria [ 1 ], viruses, parasites [ 2 – 8 ], and fungi [ 1 , 9 – 10 ], they can kill cancer cells [ 11 ]. So far, >2,500 AMPs have been described in the literature and only ≈10% of those are known to exhibit anticancer activity, according to the Antimicrobial Peptide Database ( http://aps.unmc.edu/AP/main.php ).…”

“…Torres et al synthesized Dec-NH 2 analogs with single and double substitutions, which exhibited increased resistance to degradation and lower hemolytic activity [ 9 – 10 ]. The two Dec-NH 2 analogs designed to fit a leucine zipper (LZ) template [ 25 – 26 ] presented the lowest hemolytic activity against red blood cells and maintained the antimicrobial activity of the parent template molecule vs Gram-positive bacteria, Gram-negative bacteria, and fungi.…”

“…The two Dec-NH 2 analogs designed to fit a leucine zipper (LZ) template [ 25 – 26 ] presented the lowest hemolytic activity against red blood cells and maintained the antimicrobial activity of the parent template molecule vs Gram-positive bacteria, Gram-negative bacteria, and fungi. The authors attributed these activities to the helical propensity of the designer peptides [ 9 ]. Another study further reengineered Dec-NH 2 to generate seven analogs containing single or double substitutions [ 10 ].…”

The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties

“…Peptides with higher hydrophobicity than the wild type, as well as Pol-CP-NH 2 and the analogs with higher net positive charge, slightly inhibited the growth of Hep G2 and SHSY-5Y.4 | EXPERIMENTAL PROCEDURES 4.1 | Solid-phase peptide synthesis (SPPS), purification, and analysisPeptides were synthesized on a peptide synthesizer (PS3-Sync Technologies) using the Fluorenylmethyloxycarbonyl (Fmoc) strategy in a Rink Amide resin (substitution degree of 0.52 mmol g −1 ). Procedures for synthesis, purification, analyses, and characterization are described in details by Torres et al40,Mosquito rearing and maintenance of the parasite life cycle Aedes aegypti RED strain was used in experiments due to their hypersensitivity to P. gallinaceum parasite. Mosquitoes were reared using standard laboratory procedures 13,17.…”