Design, Synthesis, Molecular Dynamics Simulation, and Functional Evaluation of a Novel Series of 26RFa Peptide Analogues Containing a Mono- or Polyalkyl Guanidino Arginine Derivative

26RFa, the endogenous QRFPR ligand, is implicated in several physiological and pathological conditions such as the regulation of glucose homeostasis and bone mineralization; hence, QRFPR ligands display therapeutic potential. At the molecular level, functional interaction occurs between residues Arg25 of 26RFa and Gln125 of QRFPR. We have designed 26RFa(20–26) analogues incorporating arginine derivatives modified by alkylated substituents. We found that the Arg25 side chain length was necessary to retain the activity of 26RFa(20–26) and that N-monoalkylation of arginine was accommodated by the QRFPR active site. In particular, [(Me)ωArg25]26RFa(20–26) (5b, LV-2186) appeared to be 25-fold more potent than 26RFa(20–26) and displayed a position in a QRFPR homology model slightly different to that of the unmodified heptapeptide. Other peptides were less potent than 26RFa(20–26), exhibited partial agonistic activity, or were totally inactive in accordance to different ligand-bound structures. In vivo, [(Me)ωAr...