The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this series of peptide derivatives identified a compound that combines effective antibacterial activity with virtually no toxicity within the same concentration range. This peptide acts against both Gram-negative and Gram-positive bacteria, including several MRSA strains, and represents an interesting lead for the development of a broadly applicable antibiotic.

Development of new antibiotics is declining whereas antibiotic resistance is rising, heralding a post-antibiotic era. Antimicrobial peptides such as gramicidin S (GS), exclusively topically used due to its hemolytic side-effect, could still be interesting as therapeutic compounds. By modifying the amino-acid composition of GS, we synthesized GS analogues. We now show that derivative VK7 has a lower MIC (7.8–31.2 μg/ml, median 15.6 μg/ml) against strains of multi-drug resistant (MDR) Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa than GS has (3.9–62.5 μg/ml, median 31.3 μg/ml). Low MICs for both VK7 and GS were observed for Staphylococcus aureus and Enterococcus faecium. VK7 showed reduced haemolysis and less lactate dehydrogenase release. All compounds were fully bactericidal at MIC values. Modification of GS enables production of novel derivatives potentially useful for systemic treatment of human infections.

Monobenzylated sugar amino acids (SAAs) that differ in ether ring size (containing an oxetane, furanoid, and pyranoid ring) were synthesized and incorporated in one of the β-turn regions of the cyclo-decapeptide gramicidin S (GS). CD, NMR spectroscopy, modeling, and X-ray diffraction reveal that the ring size of the incorporated SAA moieties determines the spatial positioning of their cis-oriented carboxyl and aminomethyl substituents, thereby subtly influencing the amide linkages with the adjacent amino acids in the sequence. Unlike GS itself, the conformational behavior of the SAA-containing peptides is solvent dependent. The derivative containing the pyranoid SAA is slightly less hydrophobic and displays a diminished haemolytic activity, but has similar antimicrobial properties as GS.

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Two series of dimeric ligands for a G-protein-coupled receptor were prepared that differ by the interconnecting spacer system. Biological evaluation revealed that both dimeric series exhibit unique biological properties relative to their monomeric counterparts.The luteinizing hormone receptor (LHR), the follicle-stimulating hormone receptor (FSHR), and the thyroid-stimulating hormone receptor (TSHR) belong to the glycoprotein hormone receptor (GpHR) family. A prominent feature of all endogenous glycoprotein ligands is that they share an identical alpha subunit and acquire their selectivity from the unique beta subunit. Recent developments in pro-fertility research have led to the discovery of several low-molecular-weight agonists for the luteinizing hormone/choriogonadotropin receptor that bind to the transmembrane (TM) region of the LHR. Interestingly, some of these agonists are also able to activate the FSHR. Several research groups have shown that ligand dimerization presents a powerful tool to increase the subtype selectivity for structurally related G-protein-coupled receptors. In this work, we applied the dimerization strategy to GpHRs and explored the effect on receptors with closely related TM regions. Two series of dimeric ligands were prepared that differ in the interconnecting spacer system. Biological evaluation revealed that both series exhibit unique selectivity properties for the LHR, originating from either decreased potency or a decreased efficacy toward the FSHR.

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