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Melanocortin Metallopeptode Combinatorial Libraries and Applications

a metallopeptode and melanocortin technology, applied in the field of metallopeptode combinatorial libraries and applications, can solve the problems of soluble library approach applicability to high affinity systems, totally misleading mice, and inability to tolerate soluble libraries, etc., to achieve rapid and efficient complexation

Inactive Publication Date: 2006-10-26
PALATIN TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a library of peptides and peptidomimetics targeted to melanocortin receptors that can be synthesized on solid phase. The peptides and peptidomimetics have a specific sequence and structure that can bind to the receptors with high affinity. The libraries can be used for research and development of drugs that target the melanocortin receptors. The peptides and peptidomimetics can be cleaved from the solid phase without losing their activity. The libraries can be synthesized using a combination of solid phase and solution phase peptides.

Problems solved by technology

Targeted disruption of the melanocortin-4 receptor results in obesity in mice.
A common artifact occasionally seen with all these resin bound libraries is altered target-specific affinity by some solid phase bound compounds in bioassays, which can result in totally misleading results.
A major limitation of the soluble library approach is its applicability to high affinity systems.

Method used

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  • Melanocortin Metallopeptode Combinatorial Libraries and Applications
  • Melanocortin Metallopeptode Combinatorial Libraries and Applications
  • Melanocortin Metallopeptode Combinatorial Libraries and Applications

Examples

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example 1

Development of a Prototype Metallopeptide Library for the Melanocortin Receptor

[0190] The library design was based on the tetrapeptide message sequence, His-Phe-Arg-Trp (6-9 sequence) (SEQ ID NO:1), of α-MSH. This sequence exists as a reverse turn, making it suitable for conversion into a metallopeptide format of this invention. In this approach metallopeptides were designed around a tripeptide N3S1 MBD designed for a rhenium metal ion. The MBD was derivatized to yield the pentapeptide Ac-His-Phe-Arg-Cys-Trp-NH2 (SEQ ID NO:8) as a putative candidate for melanocortin (“MC”) receptors. Further refinements in the structure were made in response to other considerations, including the chirality of amino acid side chains, yielding a template structure Ac-His-D-Phe-Arg-Cys-Trp-NH2. The structure of this peptide after binding to rhenium is:

[0191] The template structure was used to define a small combinatorial library utilizing split synthesis methodologies. The final template selected fo...

example 2

Design and Synthesis of Melanocortin Receptor-Specific Metallopeptide Library

[0193] The library was rationally designed based upon data relating to melanocortin receptors and peptide sequences specific to the melanocortin receptors, including melanotropin side-chain pharmacophores, D-Phe7 and Trp9, that interact with a hydrophobic network of receptor aromatic residues in transmembrane regions 4, 5, 6, and 7. Based on this design criterion, a pharmacophore for the melanocortin receptor was preliminarily defined, and a combinatorial library designed for identification of potent and receptor-selective agonists.

[0194] Based on the design criteria, the putative structure R-Aaa-Baa-L-Cys-Caa-NH2 was selected, in which each of Aaa, Baa and Caa are selected from L- or D-isomers of 2-Nal (1), Phe (2), Trp (3), Tyr (4) and Ala (5), so that any one of the foregoing can be substituted for any one of Aaa, Baa or Caa. In the nomenclature adopted for the library design, the five amino acids were...

example 3

Screening of Melanocortin Receptor-Specific Library

[0202] Metallopeptide library pools are screened for MC4-R receptor and MC1-R receptor binding activity in high throughput screening assays. The MC receptor-binding assay uses membrane preparations from B16-F1 or B16-F10 melanoma cells as the source of MC receptor. Cell membranes prepared from MC4-R-expressing 293 cells and negative control, untransfected 293 cells, are substituted for B16-F1 or B16-F10 melanoma cell membranes in MC4-R specific binding assays. The MC receptor-binding assays use the Millipore Multi-Screen System and are performed in 96-well Millipore filter plates (Durapore, 0.45 mm porosity) pre-blocked with 0.5% bovine serum albumin in phosphate buffered saline. Cell membrane preparations (12.5 μg / well) are incubated with 0.4 nM 125I-NDP-MSH in HEPES Buffer containing 0.2% bovine serum albumin. Non-specific binding is determined by addition of 10−6 M α-MSH or 10−7 M NDP-MSH. Metallopeptides to be tested are added ...

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Abstract

Melanocortin receptor-specific peptide combinatorial libraries for forming metallopeptides and metallopeptide combinatorial libraries are provided for use in biological, pharmaceutical and related applications. The combinatorial libraries are constructed of peptides constructed from naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically modified amino acids, or constructs or structures designed to mimic amino acids, in which the peptides are conformationally fixed on complexation of a metal ion-binding portion thereof with a metal ion.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a divisional application of U.S. patent application Ser. No. 10 / 049,718, entitled Melanocortin Metallopeptide Constructs, Combinatorial Libraries and Applications, filed Feb. 13, 2002, and issued as U.S. Pat. No. 7,049,398 on May 23, 2006, which application is a national entry pursuant to 37 U.S.C. § 371 of International Application No. PCT / US00 / 16396, entitled Melanocortin Metallopeptide Constructs, Combinatorial Libraries and Applications, filed Jun. 15, 2000, which in turn claims the benefit of the filing of U.S. Provisional Patent Application Ser. No. 60 / 148,994, entitled Melanocortin Receptor-Specific Metallopeptide Constructs, Combinatorial Libraries and Applications, filed on Aug. 13, 1999, and the specifications thereof are incorporated herein by reference.GOVERNMENT RIGHTS [0002] The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C40B30/06C40B40/10
CPCA61K38/00A61K51/088C07K5/1008A61K51/086C07K5/1024C07K14/665C07K5/1016
Inventor SHARMA, SHUBHSHI, YIQUNYANG, WEICAI, HUI-ZHI
Owner PALATIN TECH INC
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