Ligand-based peptide design and combinatorial peptide libraries to target G protein-coupled receptors

Gruber, Christian W., Muttenthaler, Markus and Freissmuth, Michael (2010) Ligand-based peptide design and combinatorial peptide libraries to target G protein-coupled receptors. Current Pharmaceutical Design, 16 28: 3071-3088. doi:10.2174/138161210793292474


Author Gruber, Christian W.
Muttenthaler, Markus
Freissmuth, Michael
Title Ligand-based peptide design and combinatorial peptide libraries to target G protein-coupled receptors
Journal name Current Pharmaceutical Design   Check publisher's open access policy
ISSN 1381-6128
1873-4286
Publication date 2010-09-01
Year available 2010
Sub-type Critical review of research, literature review, critical commentary
DOI 10.2174/138161210793292474
Open Access Status Not yet assessed
Volume 16
Issue 28
Start page 3071
End page 3088
Total pages 18
Place of publication Bussum, Netherlands
Publisher Bentham Science Publishers
Language eng
Abstract G protein-coupled receptors (GPCRs) are considered to represent the most promising drug targets; it has been repeatedly said that a large fraction of the currently marketed drugs elicit their actions by binding to GPCRs (with cited numbers varying from 30-50%). Closer scrutiny, however, shows that only a modest fraction of (~60) GPCRs are, in fact, exploited as drug targets, only ~20 of which are peptide-binding receptors. The vast majority of receptors in the humane genome have not yet been explored as sites of action for drugs. Given the drugability of this receptor class, it appears that opportunities for drug discovery abound. In addition, GPCRs provide for binding sites other than the ligand binding sites (referred to as the "orthosteric site"). These additional sites include (i) binding sites for ligands (referred to as "allosteric ligands") that modulate the affinity and efficacy of orthosteric ligands, (ii) the interaction surface that recruits G proteins and arrestins, (iii) the interaction sites of additional proteins (GIPs, GPCR interacting proteins that regulate G protein signaling or give rise to G protein-independent signals). These sites can also be targeted by peptides. Combinatorial and natural peptide libraries are therefore likely to play a major role in identifying new GPCR ligands at each of these sites. In particular the diverse natural peptide libraries such as the venom peptides from marine cone-snails and plant cyclotides have been established as a rich source of drug leads. High-throughput screening and combinatorial chemistry approaches allow for progressing from these starting points to potential drug candidates. This will be illustrated by focusing on the ligand-based drug design of oxytocin (OT) and vasopressin (AVP) receptor ligands using natural peptide leads as starting points. © 2010 Bentham Science Publishers Ltd.
Keyword GPCR
Drug
Ligand-based design
Peptide
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Official 2011 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Sun, 12 Dec 2010, 10:09:59 EST