NDLI: Drug Development-targeted Screening of Leptin Agonist Glycopeptides

Content Provider	Springer Nature Link
Author	Knappe, Daniel Otvos, Laszlo Pascali, Francesco Cassone, Marco Scolaro, Laura Abbadessa, Giovanni Carrillo Infante, Cynthia Kiani, Mohammad F. Donelson, Fred Hoffmann, Ralf Surmacz, Eva
Copyright Year	2008
Abstract	A glycosylated dodecapeptide fragment corresponding to the hypothalamus-active cytokine leptin exhibits agonistic properties to the leptin receptor (ObR) in vitro and penetrates into the brain in vivo. In order to characterize the drug development potential of the lead peptide and to optimize it for pharmacological applicability, a series of biochemical screening assays were custom-tailored to the leptin/ObR system. To identify peptides that bind the extracellular domain of ObR, we characterized the optimal conditions for an ELISA-type assay where the leptin fragments were immobilized to the plates. With this technology we could identify low-dose binder peptidomimetics which, according to a comparison of the conventional cell proliferation assay and a measure of metabolically active cells, revealed that agonists identified by these cellular assays may not necessarily induce the expected growth characteristics in ObR expressing cells. The original glycopeptide lead displayed a 2 h half life in 25% diluted mouse serum but poor stability in mouse brain extract. Fifteen percent of the glycopeptide crossed a dual endothelial/astrocyte cell layer (representing an in vitro model of blood-brain-barrier) in 30 min, and the coexistence of the two cell types appeared necessary to quantify the level of brain accessibility. Finally, in an in vivo mouse model, a Cy5.5 labeled glycopeptide was more evenly distributed all over the body, including the brain, than a similarly labeled full-sized leptin protein.
Starting Page	247
Ending Page	254
Page Count	8
File Format	PDF
ISSN	15733149
Journal	International Journal of Peptide Research and Therapeutics
Volume Number	14
Issue Number	3
e-ISSN	15733904
Language	English
Publisher	Springer Netherlands
Publisher Date	2008-08-05
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Molecular Medicine Pharmacology/Toxicology Pharmaceutical Sciences/Technology Polymer Sciences Animal Anatomy / Morphology / Histology Biochemistry
Content Type	Text
Resource Type	Article
Subject	Analytical Chemistry Drug Discovery Biochemistry Molecular Medicine Bioengineering

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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