title: 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.
authors.affiliation: Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Joo
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Voorhees
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D000595:Amino Acid Sequence; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D008024:Ligands; D008863:Microspheres; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020349:Surface Plasmon Resonance
chemical_list: D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D010456:Peptides, Cyclic; D011981:Receptors, Prolactin