Short arginine analogs: peptide synthesis prediction of biological effects

T. A. Dzimbova, P. Henklein, T. Bruckdorfer, R. Maier, M. Weishaupt, T. Pajpanova

Chimica oggi 2019; 37: 28

Abstract: Arginine, a semi-essential amino acid, is involved in various important metabolic processes. Moreover, Arg plays an important role in signal transduction as substrate of mammalian NO synthases, which convert arginine to citrulline and the crucial cellular signaling molecule nitric oxide. In order to conduct SAR studies on enzymes that metabolize arginine, peptides containing short-chain analogues of Arg such as 2-amino-4-guanidino-butyric acid (Agb) and 2-amino-3-guanidino-propionic acid (Agp) are interesting tools. The purpose of this work was to synthesize model peptides containing short-chain arginine analogs (Agb and Agp), to explore their proteolytic stability using docking simulations, and to computationally predict the impact of these analogs on enzymes of arginine metabolism. For the synthesis of peptides with arginine analogs, different combinations of protecting groups were used. It turned out that for the analog with the shortest chain (Agp), best results were obtained with bis-Boc protection in the side chain, whereas for Agb, mixed Pbf,Boc protection of the guanidino group is favorable. Docking results of those model peptides with trypsin correlate well with the experimentally obtained data for their hydrolysis. Our further computational docking studies suggest that short-chain analogs Agp and Agb would not interact with the following enzymes: ARG, iNOS, ADI and ADC. However, Agp and Agb should bind strongly to eNOS, AGAT and ASS, forming stable enzyme-substrate complexes, thereby potentially blocking these enzymes’ actions. Therefore, shorter arginine analogs might be used in the treatment of certain disorders, as they might block important metabolic pathways.