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The human growth hormone (GH) secreted by the anterior pituitary, binds to its cognate growth hormone receptor (GHR) and regulates longitudinal growth, organ development, metabolism of carbohydrate, protein, and lipid, as well as disease states like diabetes and cancer. GH action has also found to be a critical determinant of human lifespan. Consequently, there is considerable interest around developing an inhibitor of the GH action. The first and only antagonist of the GHR - pegvisomant - was developed at our lab more than 20 years back and is currently an FDA approved prescription drug for treating acromegaly, a condition of GH excess. Here we present the design, development, and initial characterization of a novel peptide antagonist of the human GHR. The novel antagonist termed ‘S1H’ is a 16-amino-acid peptide designed as a direct sequence mimetic of a unique fragment of the site-1 binding helix of the human GH molecule. To this end we have characterized S1H with mass spectrometry, circular dichroism spectropolarimetry, and in vitro biological assays using human cell lines expressing GHR. S1H inhibited GH induced STAT5 phosphorylation, a hallmark of GH induced intracellular signaling, in a dose-dependent manner in multiple cell lines. Furthermore, using alanine scanning mutagenesis studies, we identified a strong correlation between the helical propensity and biological activity of S1H. Taken together, our results confirm that S1H is a novel GHR inhibitor with prospective applications in human disease conditions on one hand, and also is a valuable molecular tool to study the nature of human GH-GHR interactions. We currently continue to characterize S1H for binding kinetics and in vivo effects on suppressing GH action.

A Novel Peptide Antagonist of the Human Growth Hormone Receptor