4.7 Article

Synthesis and screening of a cyclic peptide library: Discovery of small-molecule ligands against human prolactin receptor

Journal

BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 3, Pages 1026-1033

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2008.01.015

Keywords

Cyclic peptides; Combinatorial library; Partial Edman degradation; Prolactin; Prolactin receptor

Funding

  1. National Institutes of Health [R01 GM062820]

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Prolactin receptor is involved in normal lactation and reproduction; however, excessive prolactin levels can cause various reproductive disorders such as prolactinomas. Small-molecule antagonists against the human prolactin receptor (hPRLr) thus have potential clinical applications and may serve as useful molecular probes in biomedical research. In this work, we synthesized a large, support-bound cyclic peptide library (theoretical diversity of 1.2 x 10(7)) on 90-mu m TentaGel beads and screened it against the extracellular domain of hPRLr. To facilitate hit identification, each TentaGel bead was spatially segregated into outer and inner layers, with a cyclic peptide displayed on the bead surface while the bead interior contained the corresponding linear peptide. The identity of a positive bead was revealed by sequencing the linear encoding peptide within the bead by partial Edman degradation/mass spectrometry. Screening of the library resulted in 20 hits, two of which were selected for further analysis and shown to bind to hPRLr with dissociation constants of 2-3 mu M. (C) 2008 Elsevier Ltd. All rights reserved.

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