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

Laszlo Otvos, Stefan W. Vetter, Mohit Koladia, Daniel Knappe, Rico Schmidt, Eszter Ostorhazi, I. Kovalszky, Nina Bionda, Predrag Cudic, Eva Surmacz, John D. Wade, Ralf Hoffmann

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)873-882
Number of pages10
JournalAmino Acids
Volume46
Issue number4
DOIs
Publication statusPublished - Apr 1 2014

Fingerprint

Leptin
Half-Life
Peptides
Serum
Biotin
Animals
Leptin Receptors
Pharmacokinetics
Surface Plasmon Resonance
Eye Diseases
Surface plasmon resonance
Myeloid Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Tears
Inhibitory Concentration 50
Labels
Assays
Animal Models
Cells
Plasmas

Keywords

  • Anti-proliferation
  • Dissociation constant
  • Metabolic stability
  • Peptide therapeutics
  • Receptor activation

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry
  • Medicine(all)

Cite this

Otvos, L., Vetter, S. W., Koladia, M., Knappe, D., Schmidt, R., Ostorhazi, E., ... Hoffmann, R. (2014). The designer leptin antagonist peptide Allo-aca compensates for short serum half-life with very tight binding to the receptor. Amino Acids, 46(4), 873-882. https://doi.org/10.1007/s00726-013-1650-6

The designer leptin antagonist peptide Allo-aca compensates for short serum half-life with very tight binding to the receptor. / Otvos, Laszlo; Vetter, Stefan W.; Koladia, Mohit; Knappe, Daniel; Schmidt, Rico; Ostorhazi, Eszter; Kovalszky, I.; Bionda, Nina; Cudic, Predrag; Surmacz, Eva; Wade, John D.; Hoffmann, Ralf.

In: Amino Acids, Vol. 46, No. 4, 01.04.2014, p. 873-882.

Research output: Contribution to journalArticle

Otvos, L, Vetter, SW, Koladia, M, Knappe, D, Schmidt, R, Ostorhazi, E, Kovalszky, I, Bionda, N, Cudic, P, Surmacz, E, Wade, JD & Hoffmann, R 2014, 'The designer leptin antagonist peptide Allo-aca compensates for short serum half-life with very tight binding to the receptor', Amino Acids, vol. 46, no. 4, pp. 873-882. https://doi.org/10.1007/s00726-013-1650-6
Otvos, Laszlo ; Vetter, Stefan W. ; Koladia, Mohit ; Knappe, Daniel ; Schmidt, Rico ; Ostorhazi, Eszter ; Kovalszky, I. ; Bionda, Nina ; Cudic, Predrag ; Surmacz, Eva ; Wade, John D. ; Hoffmann, Ralf. / The designer leptin antagonist peptide Allo-aca compensates for short serum half-life with very tight binding to the receptor. In: Amino Acids. 2014 ; Vol. 46, No. 4. pp. 873-882.
@article{e8a47461aaed4affb40d4058f34aa043,
title = "The designer leptin antagonist peptide Allo-aca compensates for short serum half-life with very tight binding to the receptor",
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.",
keywords = "Anti-proliferation, Dissociation constant, Metabolic stability, Peptide therapeutics, Receptor activation",
author = "Laszlo Otvos and Vetter, {Stefan W.} and Mohit Koladia and Daniel Knappe and Rico Schmidt and Eszter Ostorhazi and I. Kovalszky and Nina Bionda and Predrag Cudic and Eva Surmacz and Wade, {John D.} and Ralf Hoffmann",
year = "2014",
month = "4",
day = "1",
doi = "10.1007/s00726-013-1650-6",
language = "English",
volume = "46",
pages = "873--882",
journal = "Amino Acids",
issn = "0939-4451",
publisher = "Springer Wien",
number = "4",

}

TY - JOUR

T1 - The designer leptin antagonist peptide Allo-aca compensates for short serum half-life with very tight binding to the receptor

AU - Otvos, Laszlo

AU - Vetter, Stefan W.

AU - Koladia, Mohit

AU - Knappe, Daniel

AU - Schmidt, Rico

AU - Ostorhazi, Eszter

AU - Kovalszky, I.

AU - Bionda, Nina

AU - Cudic, Predrag

AU - Surmacz, Eva

AU - Wade, John D.

AU - Hoffmann, Ralf

PY - 2014/4/1

Y1 - 2014/4/1

N2 - 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.

AB - 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.

KW - Anti-proliferation

KW - Dissociation constant

KW - Metabolic stability

KW - Peptide therapeutics

KW - Receptor activation

UR - http://www.scopus.com/inward/record.url?scp=84898927167&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84898927167&partnerID=8YFLogxK

U2 - 10.1007/s00726-013-1650-6

DO - 10.1007/s00726-013-1650-6

M3 - Article

C2 - 24366600

AN - SCOPUS:84898927167

VL - 46

SP - 873

EP - 882

JO - Amino Acids

JF - Amino Acids

SN - 0939-4451

IS - 4

ER -