ArticlePharmaceutical research2012
Kinetics and mechanisms of deamidation and covalent amide-linked adduct formation in amorphous lyophiles of a model asparagine-containing Peptide.
Article in Pharmaceutical research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 11 citations in OpenAlex.
- Article
- Isoaspartate formation and irreversible aggregation of collapsin response mediator protein 2: implications for the etiology of epilepsy and age-related cognitive decline.Research square · 2024Article
- Discovery and Control of Succinimide Formation and Accumulation at Aspartic Acid Residues in The Complementarity-Determining Region of a Therapeutic Monoclonal Antibody.Pharmaceutical research · 2023Article
- Spontaneous cross-linking of proteins at aspartate and asparagine residues is mediated via a succinimide intermediate.The Biochemical journal · 2018Article
- Mass Spectrometry Based Mechanistic Insights into Formation of Tris Conjugates: Implications on Protein Biopharmaceutics.Journal of the American Society for Mass Spectrometry · 2016Article
- Purification and identification of high molecular weight products formed during storage of neutral formulation of human insulin.Pharmaceutical research · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeAsparagine containing peptides and proteins undergo deamidation via a succinimide intermediate. This study examines the role of the succinimide in the formation of covalent, amide-linked adducts in amorphous peptide formulations.
methodsStability studies of a model peptide, Gly-Phe-L-Asn-Gly, were performed in lyophiles containing an excess of Gly-Val at 'pH' 9.5 and 40°C/40% RH. Reactant disappearance and the formation of ten different degradants were monitored by HPLC. Mechanism-based kinetic models were used to generate rate constants from the concentration vs. time profiles.
resultsDeamidation of Gly-Phe-L-Asn-Gly in lyophiles resulted in L- and D-aspartyl and isoaspartyl-containing peptides and four amide-linked adducts between the succinimide and Gly-Val. The kinetic analysis demonstrated competition between water and terminal amino groups in Gly-Val for the succinimide. The extent of covalent adduct formation was dependent on dilution effects due to its second order rate law.
conclusionThe cyclic imide formed during deamidation of asparagine containing peptides in lyophiles can also lead to covalent adducts due to reaction with other neighboring peptides. A reaction model assuming a central role for the succinimide in the formation both hydrolysis products and covalent adducts was quantitatively consistent with the kinetic data. This mechanism may contribute to the presence of covalent, non-reducible aggregates in lyophilized peptide formulations.
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