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.
Highlights
Poly(lactic-co-glycolic acid) (PLGA) is a polyester copolymer of lactic acid (LA) and glycolic acid (GA), which has been approved for drug delivery use by the United States Food and Drug
Deamidation reactions of asparagine (Asn or N) residues are among those reactions that have been reported to occur in degrading PLGA matrices [4,5,7,8,9]
The idea of catalysis by GA is based on our recent computational study of an acetic acid (AA)-catalyzed mechanism of succinimide formation from Asp residues [26], where an AA molecule acts as a proton-transfer mediator in cyclic hydrogen-bonded complexes, leading to an extensive bond reorganization
Summary
Poly(lactic-co-glycolic acid) (PLGA) is a polyester copolymer of lactic acid (LA) and glycolic acid (GA), which has been approved for drug delivery use by the United States Food and Drug. The idea of catalysis by GA is based on our recent computational study of an acetic acid (AA)-catalyzed mechanism of succinimide formation from Asp residues [26], where an AA molecule acts as a proton-transfer mediator in cyclic hydrogen-bonded complexes, leading to an extensive bond reorganization. By this mechanism, it was successfully explained why the backbone amide nitrogen. Two-step mechanism for succinimide formation from an Asn residue
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