Inhibition of dipeptidylpeptidase-IV by 2-S-cyanopyrrolidine inhibitors of prolyl endopeptidase

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Abstract

Many regulatory neuropeptides contain a large amount of proline residues. The unique proline peptide bond conformation protects these peptides from enzymatic degradation; therefore enzymes cleaving the proline peptide bonds in neuropeptides are of particular interest. The abnormal activity of serine peptidases that cleave peptides at the carboxyl group of proline residues prolyl endopeptidase (PEP) and dipeptidyl peptidase IV (DPP-IV) were observed in patients with anxiety disorders. PEP is involved in the maturation and degradation of neuropeptides and peptide hormones, it also is associated with the regulation of blood pressure and various disorders of the central nervous system. DPP-IV is involved in many physiological processes, in particular in glucose homeostasis in type II diabetes and immunity. When studying the metabolism of the N-acyl derivative of the aminoacyl-2-cyanopyrrolidine PEP inhibitor a decreasing in the activity of DPP-IV at the initial time was detected. This was an unexpected effect observed for inhibitors of the general formula X-Y-2-S-cyanopyrrolidine, where X represents the N-protective group and Y represents the amino acid (any besides glycine and proline). Molecular dynamics simulations of inhibitor complexes with proteases revealed the possibility of PEP inhibitors binding in the DPP-IV active site with hydrogen bonds and hydrophobic interactions that allow linkage of the nitrile group with the catalytic serine residue in the DPP-IV active site. The present study opens the prospect of creating new pharmacologically active ligands of PEP and DPP-IV.

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About the authors

G. I. Makarov

South Ural State University

Author for correspondence.
Email: makarovgi@susu.ru
Russian Federation, prosp. Lenina 76, Chelyabinsk, 454080

N. N. Zolotov

Research Zakusov Institute of Pharmacology

Email: makarovgi@susu.ru
Russian Federation, ul. Baltiyskaya 8, Moscow, 125315

V. F. Pozdnev

Institute of Biomedical Chemistry

Email: makarovgi@susu.ru
Russian Federation, ul. Pogodinskaya 10/8, Moscow, 119121

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Supplementary files

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2. Supplementary
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3. Fig. 1. Structures of peptidase inhibitors studied in this work.

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4. Fig. 2. Hydrogen bonds formed by inhibitors with the active site of PEP. AA is the corresponding amino acid residue of the inhibitor, Protect is the protecting group. See also Table S1 in the supplementary material.

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5. Fig. 3. Conformations of pyrrolidone prolyl endopeptidase inhibitors (shown in dark blue) in the active site of PEP obtained by molecular dynamics simulation. Hydrogen bonds are shown by black dotted lines. The near hydrophobic zone is shown in yellow, the hydrophobic cavity in blue, and the negative protrusion in red. (a) – HGlyPrn; (b) – CbzGlyPrn; (c) – CbzMetPrn; (d) – SucMetPrn.

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6. Fig. 4. Conformations of pyrrolidone prolyl endopeptidase inhibitors (shown in dark blue) in the active site of DPP4 obtained by molecular dynamics simulation. Hydrogen bonds are shown by black dotted lines. The near hydrophobic zone is shown in yellow, the hydrophobic cavity in blue, and the negative protrusion in red. (a) – HGlyPrn; (b) – CbzGlyPrn; (c) – CbzMetPrn; (d) – SucMetPrn.

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7. Fig. 5. General procedure for the synthesis of N-protected dipeptide carbonitriles. R1 is an amino acid side chain, R2 is tert-butyl or benzyl.

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