1.Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH.
Hayashi R1, Kitajima T1, Mizuguchi H1, Fujimoto M1, Yamaguchi A1, Koga S1, Koga Y1, Osada S1, Kodama H2. Bioorg Med Chem. 2014 Aug 1;22(15):3824-8. doi: 10.1016/j.bmc.2014.06.048. Epub 2014 Jul 8.
While stimulation of formyl peptide receptors (FPRs) on the surface of human neutrophils induces several immune responses, under conditions of continuous activation of the receptor by agonists such as formyl-Met-Leu-Phe-OH (fMLP), neutrophil-dependent tissue damage ensues. Thus, FPR antagonists could be anticipated as drugs for FPR-related disease. In this study, Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH (Boc-FlFlF), one of several FPR subtype selective antagonists, was chosen and the positions at the Phe residues were optimized. We found that substitution with unnatural amino acids resulted in an improvement of two orders of magnitude. The most potent antagonist indicated FPR subtype selectivity at 1 μM. In addition to finding a potent antagonist, the structure-activity trends observed in this study should be valuable in designing a new type of FPR subtype selective antagonist.
2.A conformation-selective IR-UV study of the dipeptides Ac-Phe-Ser-NH2 and Ac-Phe-Cys-NH2: probing the SH···O and OH···O hydrogen bond interactions.
Yan B1, Jaeqx S, van der Zande WJ, Rijs AM. Phys Chem Chem Phys. 2014 Jun 14;16(22):10770-8. doi: 10.1039/c4cp00810c.
The conformational preferences of peptides are mainly controlled by the stabilizing effect of intramolecular interactions. In peptides with polar side chains, not only the backbone but also the side chain interactions determine the resulting conformations. In this paper, the conformational preferences of the capped dipeptides Ac-Phe-Ser-NH2 (FS) and Ac-Phe-Cys-NH2 (FC) are resolved under laser-desorbed jet cooling conditions using IR-UV ion dip spectroscopy and density functional theory (DFT) quantum chemistry calculations. As serine (Ser) and cysteine (Cys) only differ in an OH (Ser) or SH (Cys) moiety; this subtle alteration allows us to study the effect of the difference in hydrogen bonding for an OH and SH group in detail, and its effect on the secondary structure. IR absorption spectra are recorded in the NH stretching region (3200-3600 cm(-1)). In combination with quantum chemical calculations the spectra provide a direct view of intramolecular interactions.
