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Int. J. Mol. Sci. 2017, 18(2), 429; doi:10.3390/ijms18020429

Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain

Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
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Academic Editors: Habil. Mihai V. Putz and Christo Z. Christov
Received: 20 December 2016 / Revised: 17 January 2017 / Accepted: 10 February 2017 / Published: 16 February 2017
(This article belongs to the Special Issue Chemical Bond and Bonding 2016)
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Abstract

The Asn-Gly-Arg (NGR) motif and its deamidation product isoAsp-Gly-Arg (isoDGR) have recently attracted considerable attention as tumor-targeting ligands. Because an NGR-containing peptide and the corresponding isoDGR-containing peptide target different receptors, the spontaneous NGR deamidation can be used in dual targeting strategies. It is well known that the Asn deamidation proceeds via a succinimide derivative. In the present study, we computationally investigated the mechanism of succinimide formation from a cyclic peptide, c[CH2CO-NGRC]-NH2, which has recently been shown to undergo rapid deamidation in a phosphate buffer. An H2PO4 ion was explicitly included in the calculations. We employed the density functional theory using the B3LYP functional. While geometry optimizations were performed in the gas phase, hydration Gibbs energies were calculated by the SM8 (solvation model 8) continuum model. We have found a pathway leading to the five-membered ring tetrahedral intermediate in which both the H2PO4 ion and the Arg side chain act as catalyst. This intermediate, once protonated at the NH2 group on the five-membered ring, was shown to easily undergo NH3 elimination leading to the succinimide formation. This study is the first to propose a possible catalytic role for the Arg side chain in the NGR deamidation. View Full-Text
Keywords: Asn-Gly-Arg (NGR) motif; isoAsp-Gly-Arg (isoDGR) motif; tumor-targeting ligands; deamidation; nonenzymatic reaction; succinimide intermediate; phosphate buffer catalysis; intramolecular catalysis; computational chemistry; density functional theory Asn-Gly-Arg (NGR) motif; isoAsp-Gly-Arg (isoDGR) motif; tumor-targeting ligands; deamidation; nonenzymatic reaction; succinimide intermediate; phosphate buffer catalysis; intramolecular catalysis; computational chemistry; density functional theory
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Kirikoshi, R.; Manabe, N.; Takahashi, O. Succinimide Formation from an NGR-Containing Cyclic Peptide: Computational Evidence for Catalytic Roles of Phosphate Buffer and the Arginine Side Chain. Int. J. Mol. Sci. 2017, 18, 429.

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