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

Abstract:

: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 1.2x10(7)) on 90-microm 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 microM.

journal_name

Bioorg Med Chem

authors

Liu T,Joo SH,Voorhees JL,Brooks CL,Pei D

doi

10.1016/j.bmc.2008.01.015

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

1026-33

issue

3

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(08)00017-5

journal_volume

17

pub_type

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