کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2485877 | 1114369 | 2007 | 19 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The Role of the Cyclic Imide in Alternate Degradation Pathways for AsparagineâContaining Peptides and Proteins
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: The Role of the Cyclic Imide in Alternate Degradation Pathways for AsparagineâContaining Peptides and Proteins The Role of the Cyclic Imide in Alternate Degradation Pathways for AsparagineâContaining Peptides and Proteins](/preview/png/2485877.png)
چکیده انگلیسی
Peptides and proteins exhibit enhanced reactivity at asparagine residues due to the formation of a reactive succinimide intermediate that produces normal and isoaspartyl deamidation products along with significant racemization. This study examines the potential for attack of amine nucleophiles at the succinimide carbonyls to generate alternate decomposition products, depending on the nucleophile involved in the reaction. The reactions of the model peptides PheâAsnâGly (FNG) and PheâisoAsnâGly (FisoNG) were explored as a function of pH (8.5-10.5) in the presence and absence of ammonia buffer (0.2-2Â M) using an isocratic HPLC method to monitor reactant disappearance and product formation. In addition to deamidation to form isoAsp and Asp peptides, two additional types of reactions were found to occur via the succinimide intermediate under these conditions. Backâreaction of the succinimide with ammonia led to peptide backbone isomerization while intramolecular attack by the amino terminus produced diketopiperazines. A kinetic model assuming a central role for the succinimide intermediate was derived to fit the concentration versus time data. These studies implicate the cyclic imide as a key intermediate in the formation of alternate peptide and protein degradants, including possible covalent amideâlinked aggregates that may form from intermolecular attack of the cyclic imide by neighboring amino groups. © 2007 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2667-2685, 2007
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 96, Issue 10, October 2007, Pages 2667-2685
Journal: Journal of Pharmaceutical Sciences - Volume 96, Issue 10, October 2007, Pages 2667-2685
نویسندگان
Michael P. DeHart, Bradley D. Anderson,