کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2484482 | 1114313 | 2016 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Structure, Aggregation, and Activity of a Covalent Insulin Dimer Formed During Storage of Neutral Formulation of Human Insulin
ترجمه فارسی عنوان
ساختار، همگرائی و فعالیت یک دیمر انسولین کووالانسی شکل گرفته در طول ذخیره سازی فرمولاسیون غیرطبیعی انسولین انسانی
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کلمات کلیدی
HMWPSLSPDBSAXSTOCSYDLSNOESYNOEThT assayNuclear Overhauser Effect SpectroscopY - Spectroscopy اثر Overhauser هسته ایnuclear overhauser effect - اثر بیش از حد هسته ایX-ray crystallography - بلورنگاری پرتو-ایکسTotal correlation spectroscopy - طیف سنجی مجموع همبستگیFibrillation - فیبریلاسیونSmall-angle X-ray scattering - پراکندگی اشعه ایکس با زاویه کوچکstatic light scattering - پراکندگی نور استاتیکDynamic Light Scattering - پراکندگی نور دینامیکی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
چکیده انگلیسی
A specific covalently linked dimeric species of insulin high molecular weight products (HMWPs), formed during prolonged incubation of a neutral pharmaceutical formulation of human insulin, were characterized in terms of tertiary structure, self-association, biological activity, and fibrillation properties. The dimer was formed by a covalent link between A21Asn and B29Lys. It was analyzed using static and dynamic light scattering and small-angle X-ray scattering to evaluate its self-association behavior. The tertiary structure was obtained using nuclear magnetic resonance and X-ray crystallography. The biological activity of HMWP was determined using 2 in vitro assays, and its influence on fibrillation was investigated using Thioflavin T assays. The dimer's tertiary structure was nearly identical to that of the noncovalent insulin dimer, and it was able to form hexamers in the presence of zinc. The dimer exhibited reduced propensity for self-association in the absence of zinc but significantly postponed the onset of fibrillation in insulin formulations. Consistent with its dimeric state, the tested species of HMWP showed little to no biological activity in the used assays. This study is the first detailed characterization of a specific type of human insulin HMWP formed during storage of a marketed pharmaceutical formulation. These results indicate that this specific type of HMWP is unlikely to antagonize the physical stability of the formulation, as HMWP retained a tertiary structure similar to the noncovalent dimer and participated in hexamer assembly in the presence of zinc. In addition, increasing amounts of HMWP reduce the rate of insulin fibrillation.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 105, Issue 4, April 2016, Pages 1376-1386
Journal: Journal of Pharmaceutical Sciences - Volume 105, Issue 4, April 2016, Pages 1376-1386
نویسندگان
Christian Fogt Hjorth, Mathias Norrman, Per-Olof Wahlund, Andrew J. Benie, Bent O. Petersen, Christian M. Jessen, Thomas Ã
. Pedersen, Kirsten Vestergaard, Dorte B. Steensgaard, Jan Skov Pedersen, Helle Naver, FrantiÅ¡ek Hubálek, Christian Poulsen,