Novel anoplin‐based (lipo)‐peptide models show potent antimicrobial activity

The subject of this study is the synthesis and biological evaluation of anoplin‐based (Gly‐Leu‐Leu3‐Lys‐Arg5‐Ile‐Lys‐Thr8‐Leu‐Leu‐NH2)—designed (lipo)‐peptides, aiming at the development of new antibiotic substances. The design of synthetic compounds based on natural bioactive molecules is an optimistic strategy for the development of new pharmaceutics. Antimicrobial peptides (AMPs) and (lipo)‐peptides are two classes of promising compounds, with characteristics that allow them to express their activity by differentiated mechanisms of action. On this basis, anoplin, a natural AMP, was used as a scaffold to design five peptides and seven lipopeptide analogs of them. Substitutions were made on residues Leu3 and Arg5 of the interphase and on Thr8 of the polar phase, as well as N‐terminus conjunctions with octanoic and decanoic acid. The outcome of the biological evaluation revealed that some analogs might have substantial clinical potential. Specifically, Ano 1‐F, Ano 3‐F, Ano 4‐C10, and Ano 5‐F are strongly active against Gram‐negative bacteria at minimum inhibitory concentration (MIC) values of 3 μg/ml, while Ano 4‐F is active against Gram‐positive bacteria at 1 μg/ml. Ano 2‐C10, C10‐Gly‐Leu‐Lys3‐Lys‐Ile5‐Ile‐Lys‐Lys8‐Leu‐Leu‐NH2, is the most promising compound (MIC = 0.5 μg/ml) for the development of new pharmaceutics. The conformational features of the synthetic peptides were investigated by circular dichroism spectroscopy, and their physicochemical parameters were calculated. Our study shows that appropriate substitutions in the anoplin sequence in combination with Nα‐acylation may lead to new effective AMPs. In this study, novel analogs of anoplin Gly‐Leu‐Leu‐Lys‐Arg‐Ile‐Lys‐Thr‐Leu‐Leu‐NH2 were designed, prepared, and examined for their antimicrobial and hemolytic activity. Our study shows that appropriate substitutions in the anoplin sequence as well as the N‐terminus conjunction with octanoic and decanoic acid may lead to the preparation of effective antimicrobial compounds.