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  3. A novel peptide antagonist of the human growth hormone receptor

A novel peptide antagonist of the human growth hormone receptor

  • J Biol Chem. 2021 Jan-Jun:296:100588. doi: 10.1016/j.jbc.2021.100588.
Reetobrata Basu 1,  Khairun Nahar 2,  Prateek Kulkarni 3,  Olivia Kerekes 2,  Maya Sattler 4,  Zachary Hall 2,  Sebastian Neggers 5,  Justin M Holub 6,  John J Kopchick 7
Affiliations

Affiliations

  • 1 Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA; Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA.
  • 2 Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA.
  • 3 Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA; Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA.
  • 4 Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA; Honors Tutorial College, Ohio University, Athens, Ohio, USA.
  • 5 Department of Medicine, Endocrinology Section, Erasmus University Medical Centre, Rotterdam, the Netherlands.
  • 6 Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA; Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio, USA; Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA. Electronic address: holub@ohio.edu.
  • 7 Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA; Edison Biotechnology Institute, Ohio University, Athens, Ohio, USA; Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA. Electronic address: kopchick@ohio.edu.
PMID: 33774052 DOI: 10.1016/j.jbc.2021.100588
Abstract

Excess circulating human growth hormone (hGH) in vivo is linked to metabolic and growth disorders such as Cancer, diabetes, and acromegaly. Consequently, there is considerable interest in developing antagonists of hGH action. Here, we present the design, synthesis, and characterization of a 16-residue peptide (site 1-binding helix [S1H]) that inhibits hGH-mediated STAT5 phosphorylation in cultured cells. S1H was designed as a direct sequence mimetic of the site 1 mini-helix (residues 36-51) of wild-type hGH and acts by inhibiting the interaction of hGH with the human growth hormone receptor (hGHR). In vitro studies indicated that S1H is stable in human serum and can adopt an α-helix in solution. Our results also show that S1H mitigates phosphorylation of STAT5 in cells co-treated with hGH, reducing intracellular STAT5 phosphorylation levels to those observed in untreated controls. Furthermore, S1H was found to attenuate the activity of the hGHR and the human Prolactin receptor, suggesting that this peptide acts as an antagonist of both lactogenic and somatotrophic hGH actions. Finally, we used alanine scanning to determine how discrete Amino acids within the S1H sequence contribute to its structural organization and biological activity. We observed a strong correlation between helical propensity and inhibitory effect, indicating that S1H-mediated antagonism of the hGHR is largely dependent on the ability for S1H to adopt an α-helix. Taken together, these results show that S1H not only acts as a novel peptide-based antagonist of the hGHR but can also be applied as a chemical tool to study the molecular nature of hGH-hGHR interactions.

Keywords

GH receptor; growth hormone; peptide antagonist; peptide mimetic; site 1-binding helix.

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    99.29%, 人生长激素受体拮抗剂
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