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Short arginine analogs: peptide synthesis and prediction of biological effects – Efficient synthesis of peptides containing short analogs of arginine and stability evaluation with docking. Prediction of biological effects of short arginine analogs using computational methods.

corresponding

TATYANA A. DZIMBOVA1, PETRA HENKLEIN2, THOMAS BRUCKDORFER3, RAIMUND M. MAIER3, MARKUS W. WEISHAUPT3*, TAMARA I. PAJPANOVA4*
*Corresponding authors
1. South-West University “Neofit Rilski”, Faculty of Public Health, Health Care and Sport, Blagoevgrad, Bulgaria
2. Charité – Universitätsmedizin Berlin, Institut für Biochemie, Berlin, Germany
3. Iris Biotech GmbH, Marktredwitz, Germany
4. Institute of Molecular Biology “Roumen Tsanev”, Bulgarian Academy of Sciences, Sofia, Bulgaria

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.


INTRODUCTION

Arginine contains four nitrogen atoms per molecule, making it the richest carrier of nitrogen in the mammalian organism. It is a semi-essential amino acid included in different areas of cell physiology and metabolism. Arginine is not considered as an essential amino acid, because the human body can synthesize it de novo from glutamine, glutamic acid and proline. However, plasma levels of Arg are mainly determined by nutritional intake, as the speed of its biosynthesis does not increase to compensate its depletion or inadequate supply (1,2). Arginine is synthesized from citrulline in mammals through an enzyme-catalyzed two-step process. One of the enzymes involved is argininosuccinate synthetase (ASS).

After entering the body, arginine is immediately absorbed. About half of the ingested arginine is converted to ornithine by arginase (ARG) (3). Ornithine, in turn, can be metabolized to glutamic acid, proline, or through the enzyme ornithine decarboxylase to polyamines.

Arginine is both a precursor in the synthesis of proteins, and in the biosynthesis of small molecules such as nitric oxide, urea, creatine and agmatine (4), involvi ...



 

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