Design and Development of a Peptide-based Adiponectin Receptor Agonist for Cancer Treatment

Laszlo Otvos, Eva Haspinger, Francesca LaRussa, Federica Maspero, Patrizia Graziano, Ilona Kovalszky, Sandor Lovas, Kaushik Nama, Ralf Hoffmann, Daniel Knappe, Marco Cassone, John Wade, Eva Surmacz

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

Background: Adiponectin, a fat tissue-derived adipokine, exhibits beneficial effects against insulin resistance, cardiovascular disease, inflammatory conditions, and cancer. Circulating adiponectin levels are decreased in obese individuals, and this feature correlates with increased risk of developing several metabolic, immunological and neoplastic diseases. Thus, pharmacological replacement of adiponectin might prove clinically beneficial, especially for the obese patient population. At present, adiponectin-based therapeutics are not available, partly due to yet unclear structure/function relationships of the cytokine and difficulties in converting the full size adiponectin protein into a viable drug. Results: We aimed to generate adiponectin-based short peptide that can mimic adiponectin action and be suitable for preclinical and clinical development as a cancer therapeutic. Using a panel of 66 overlapping 10 amino acid-long peptides covering the entire adiponectin globular domain (residues 105-254), we identified the 149-166 region as the adiponectin active site. Three-dimensional modeling of the active site and functional screening of additional 330 peptide analogs covering this region resulted in the development of a lead peptidomimetic, ADP 355 (H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH2). In several adiponectin receptor-positive cancer cell lines, ADP 355 restricted proliferation in a dose-dependent manner at 100 nM-10 microM concentrations (exceeding the effects of 50 ng/mL globular adiponectin). Furthermore, ADP 355 modulated several key signaling pathways (AMPK, Akt, STAT3, ERK1/2) in an adiponectin-like manner. siRNA knockdown experiments suggested that ADP 355 effects can be transmitted through both adiponectin receptors, with a greater contribution of AdipoR1. In vivo, intraperitoneal administration of 1 mg/kg/day ADP 355 for 28 days suppressed the growth of orthotopic human breast cancer xenografts by ~31%. The peptide displayed excellent stability (at least 30 min) in mouse blood or serum and did not induce gross toxic effects at 5-50 mg/kg bolus doses in normal CBA/J mice. Conclusions: ADP 355 is a first-in-class adiponectin receptor agonist. Its biological activity, superior stability in biological fluids as well as acceptable toxicity profile indicate that the peptidomimetic represents a true lead compound for pharmaceutical development to replace low adiponectin levels in cancer and other malignancies.

Original languageEnglish
Pages (from-to)90
Number of pages1
JournalBMC Biotechnology
DOIs
StateAccepted/In press - Oct 5 2011

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Adiponectin Receptors
Adiponectin
Peptides
Adenosine Diphosphate
Neoplasms
Therapeutics
Peptidomimetics
leucyltyrosine
phenylalanylalanine
Catalytic Domain
Inbred CBA Mouse
AMP-Activated Protein Kinases
Adipokines
Poisons
Immune System Diseases
Heterografts
Pharmaceutical Preparations
Small Interfering RNA

All Science Journal Classification (ASJC) codes

  • Biotechnology

Cite this

Otvos, L., Haspinger, E., LaRussa, F., Maspero, F., Graziano, P., Kovalszky, I., ... Surmacz, E. (Accepted/In press). Design and Development of a Peptide-based Adiponectin Receptor Agonist for Cancer Treatment. BMC Biotechnology, 90. https://doi.org/10.1186/1472-6750-11-90

Design and Development of a Peptide-based Adiponectin Receptor Agonist for Cancer Treatment. / Otvos, Laszlo; Haspinger, Eva; LaRussa, Francesca; Maspero, Federica; Graziano, Patrizia; Kovalszky, Ilona; Lovas, Sandor; Nama, Kaushik; Hoffmann, Ralf; Knappe, Daniel; Cassone, Marco; Wade, John; Surmacz, Eva.

In: BMC Biotechnology, 05.10.2011, p. 90.

Research output: Contribution to journalArticle

Otvos, L, Haspinger, E, LaRussa, F, Maspero, F, Graziano, P, Kovalszky, I, Lovas, S, Nama, K, Hoffmann, R, Knappe, D, Cassone, M, Wade, J & Surmacz, E 2011, 'Design and Development of a Peptide-based Adiponectin Receptor Agonist for Cancer Treatment', BMC Biotechnology, pp. 90. https://doi.org/10.1186/1472-6750-11-90
Otvos, Laszlo ; Haspinger, Eva ; LaRussa, Francesca ; Maspero, Federica ; Graziano, Patrizia ; Kovalszky, Ilona ; Lovas, Sandor ; Nama, Kaushik ; Hoffmann, Ralf ; Knappe, Daniel ; Cassone, Marco ; Wade, John ; Surmacz, Eva. / Design and Development of a Peptide-based Adiponectin Receptor Agonist for Cancer Treatment. In: BMC Biotechnology. 2011 ; pp. 90.
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AU - Maspero, Federica

AU - Graziano, Patrizia

AU - Kovalszky, Ilona

AU - Lovas, Sandor

AU - Nama, Kaushik

AU - Hoffmann, Ralf

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N2 - Background: Adiponectin, a fat tissue-derived adipokine, exhibits beneficial effects against insulin resistance, cardiovascular disease, inflammatory conditions, and cancer. Circulating adiponectin levels are decreased in obese individuals, and this feature correlates with increased risk of developing several metabolic, immunological and neoplastic diseases. Thus, pharmacological replacement of adiponectin might prove clinically beneficial, especially for the obese patient population. At present, adiponectin-based therapeutics are not available, partly due to yet unclear structure/function relationships of the cytokine and difficulties in converting the full size adiponectin protein into a viable drug. Results: We aimed to generate adiponectin-based short peptide that can mimic adiponectin action and be suitable for preclinical and clinical development as a cancer therapeutic. Using a panel of 66 overlapping 10 amino acid-long peptides covering the entire adiponectin globular domain (residues 105-254), we identified the 149-166 region as the adiponectin active site. Three-dimensional modeling of the active site and functional screening of additional 330 peptide analogs covering this region resulted in the development of a lead peptidomimetic, ADP 355 (H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSer-Phe-Ala-DSer-NH2). In several adiponectin receptor-positive cancer cell lines, ADP 355 restricted proliferation in a dose-dependent manner at 100 nM-10 microM concentrations (exceeding the effects of 50 ng/mL globular adiponectin). Furthermore, ADP 355 modulated several key signaling pathways (AMPK, Akt, STAT3, ERK1/2) in an adiponectin-like manner. siRNA knockdown experiments suggested that ADP 355 effects can be transmitted through both adiponectin receptors, with a greater contribution of AdipoR1. In vivo, intraperitoneal administration of 1 mg/kg/day ADP 355 for 28 days suppressed the growth of orthotopic human breast cancer xenografts by ~31%. The peptide displayed excellent stability (at least 30 min) in mouse blood or serum and did not induce gross toxic effects at 5-50 mg/kg bolus doses in normal CBA/J mice. Conclusions: ADP 355 is a first-in-class adiponectin receptor agonist. Its biological activity, superior stability in biological fluids as well as acceptable toxicity profile indicate that the peptidomimetic represents a true lead compound for pharmaceutical development to replace low adiponectin levels in cancer and other malignancies.

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