title: Glycolic acid-catalyzed deamidation of asparagine residues in degrading PLGA matrices: a computational study.
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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. manabe@tohoku-pharm.ac.jp.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Manabe
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. kirikoshi@tohoku-pharm.ac.jp.
authors.forename: Ryota
authors.initials: R
authors.lastname: Kirikoshi
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. ohgi@tohoku-pharm.ac.jp.
authors.forename: Ohgi
authors.initials: O
authors.lastname: Takahashi
mesh_terms: D000641:Ammonia / Q000737:chemistry; D001216:Asparagine / Q000737:chemistry*; D002384:Catalysis; D003500:Cyclization; D006016:Glycolates / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011506:Proteins / Q000737:chemistry
chemical_list: D006016:Glycolates; D010455:Peptides; D011506:Proteins; C031149:glycolic acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D001216:Asparagine; D000641:Ammonia
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