NDLI: The designer leptin antagonist peptide Allo-aca compensates for short serum half-life with very tight binding to the receptor

Content Provider	Springer Nature Link
Author	Otvos, Laszlo Vetter, Stefan W. Koladia, Mohit Knappe, Daniel Schmidt, Rico Ostorhazi, Eszter Kovalszky, Ilona Bionda, Nina Cudic, Predrag Surmacz, Eva Wade, John D. Hoffmann, Ralf
Copyright Year	2013
Abstract	The leptin receptor antagonist peptide Allo-aca exhibits picomolar activities in various cellular systems and sub-mg/kg subcutaneous efficacies in animal models making it a prime drug candidate and target validation tool. Here we identified the biochemical basis for its remarkable in vivo activity. Allo-aca decomposed within 30 min in pooled human serum and was undetectable beyond the same time period from mouse plasma during pharmacokinetic measurements. The C max of 8.9 μg/mL at 5 min corresponds to approximately 22 % injected peptide present in the circulation. The half-life was extended to over 2 h in bovine vitreous fluid and 10 h in human tears suggesting potential efficacy in ophthalmic diseases. The peptide retained picomolar anti-proliferation activity against a chronic myeloid leukemia cell line; addition of a C-terminal biotin label increased the IC50 value by approximately 200-fold. In surface plasmon resonance assays with the biotin-labeled peptide immobilized to a NeutrAvidin-coated chip, Allo-aca exhibited exceptionally tight binding to the binding domain of the human leptin receptor with k a = 5 × 105 M−1 s−1 and k diss = 1.5 × 10−4 s−1 values. Peptides excel in terms of high activity and selectivity to their targets, and may activate or inactivate receptor functions considerably longer than molecular turnovers that take place in experimental animals.
Starting Page	873
Ending Page	882
Page Count	10
File Format	PDF
ISSN	09394451
Journal	Amino Acids
Volume Number	46
Issue Number	4
e-ISSN	14382199
Language	English
Publisher	Springer Vienna
Publisher Date	2013-12-24
Publisher Place	Vienna
Access Restriction	Subscribed
Subject Keyword	Anti-proliferation Dissociation constant Metabolic stability Peptide therapeutics Receptor activation Biochemistry Analytical Chemistry Biochemical Engineering Life Sciences Proteomics Neurobiology
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Biochemistry Clinical Biochemistry

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