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Int. J. Mol. Sci. 2015, 16(4), 7261-7272; doi:10.3390/ijms16047261

Glycolic Acid-Catalyzed Deamidation of Asparagine Residues in Degrading PLGA Matrices: A Computational Study

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
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Academic Editor: Habil. Mihai V. Putz
Received: 17 February 2015 / Revised: 24 March 2015 / Accepted: 26 March 2015 / Published: 31 March 2015
(This article belongs to the Special Issue Chemical Bond and Bonding 2015)
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Abstract

Poly(lactic-co-glycolic acid) (PLGA) is a strong candidate for being a drug carrier in drug delivery systems because of its biocompatibility and biodegradability. However, in degrading PLGA matrices, the encapsulated peptide and protein drugs can undergo various degradation reactions, including deamidation at asparagine (Asn) residues to give a succinimide species, which may affect their potency and/or safety. Here, we show computationally that glycolic acid (GA) in its undissociated form, which can exist in high concentration in degrading PLGA matrices, can catalyze the succinimide formation from Asn residues by acting as a proton-transfer mediator. A two-step mechanism was studied by quantum-chemical calculations using Ace-Asn-Nme (Ace = acetyl, Nme = NHCH3) as a model compound. The first step is cyclization (intramolecular addition) to form a tetrahedral intermediate, and the second step is elimination of ammonia from the intermediate. Both steps involve an extensive bond reorganization mediated by a GA molecule, and the first step was predicted to be rate-determining. The present findings are expected to be useful in the design of more effective and safe PLGA devices. View Full-Text
Keywords: peptide and protein drugs; asparagine residue; deamidation; succinimide; PLGA; glycolic acid catalysis; computational chemistry; double proton transfer; concerted bond reorganization peptide and protein drugs; asparagine residue; deamidation; succinimide; PLGA; glycolic acid catalysis; computational chemistry; double proton transfer; concerted bond reorganization
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Manabe, N.; Kirikoshi, R.; Takahashi, O. Glycolic Acid-Catalyzed Deamidation of Asparagine Residues in Degrading PLGA Matrices: A Computational Study. Int. J. Mol. Sci. 2015, 16, 7261-7272.

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