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.
Keywords: GPCR, drug, ligand-based design, peptide, cyclotide, conotoxin, oxytocin, vasopressin
Current Pharmaceutical Design
Title: Ligand-Based Peptide Design and Combinatorial Peptide Libraries to Target G Protein-Coupled Receptors
Volume: 16 Issue: 28
Author(s): Christian W. Gruber, Markus Muttenthaler and Michael Freissmuth
Affiliation:
Keywords: GPCR, drug, ligand-based design, peptide, cyclotide, conotoxin, oxytocin, vasopressin
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.
Export Options
About this article
Cite this article as:
W. Gruber Christian, Muttenthaler Markus and Freissmuth Michael, Ligand-Based Peptide Design and Combinatorial Peptide Libraries to Target G Protein-Coupled Receptors, Current Pharmaceutical Design 2010; 16 (28) . https://dx.doi.org/10.2174/138161210793292474
DOI https://dx.doi.org/10.2174/138161210793292474 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Acute and Sub-acute Oral Toxicity Assessment of a Standardized Polyherbal Preparation POL-6 in Rats
The Natural Products Journal GABAB Receptors as Potential Therapeutic Targets
Current Drug Targets - CNS & Neurological Disorders Current Understanding of Polymyxin B Applications in Bacteraemia/ Sepsis Therapy Prevention: Clinical, Pharmaceutical, Structural and Mechanistic Aspects
Anti-Infective Agents in Medicinal Chemistry Role of Heme Oxygenase-1 in Cardiovascular Function
Current Pharmaceutical Design Pharmacodynamics and Pharmacokinetics of Antifungals for Treatment of Invasive Aspergillosis
Current Pharmaceutical Design Adverse Drug Reactions: Trends in a Tertiary Care Hospital
Current Drug Safety Supramolecular Chiro-Biomedical Aspect of β-Blockers in Drug Development
Current Drug Targets Psychiatric Disorders Associated with FXTAS
Current Psychiatry Reviews Unraveling Monoamine Receptors Involved in the Action of Typical and Atypical Antipsychotics on Glutamatergic and Serotonergic Transmission in Prefrontal Cortex
Current Pharmaceutical Design Management of Acute Aluminum Phosphide Poisoning: Has Anything Changed?
Drug Metabolism Letters Tear Film, Conjunctival and Corneal Modifications Induced by Glaucoma Treatment
Current Medicinal Chemistry Cardiac and Renal Nitric Oxide in the Adaptation to Hypovolemic Shock
Current Enzyme Inhibition Endothelin Receptors in Gastrointestinal Smooth Muscle
Current Protein & Peptide Science 4-Aminocyclopentane-1,3-diols as Platforms for Diversity: Synthesis of Anandamide Analogs
Medicinal Chemistry Targeting the Endocannabinod System to Limit Myocardial and Cerebral Ischemic and Reperfusion Injury
Current Pharmaceutical Biotechnology Pharmacological Treatment of Hypertension in Pregnancy
Current Pharmaceutical Design The Development of Medications for Alcohol-Use Disorders Targeting the GABAB Receptor System
Recent Patents on CNS Drug Discovery (Discontinued) Functions of Third Extracellular Loop and Helix 8 of Family B GPCRs Complexed with RAMPs and Characteristics of their Receptor Trafficking
Current Protein & Peptide Science Norepinephrine in Goal-Directed Fluid Therapy During General Anesthesia in Elderly Patients Undergoing Spinal Operation: Determining Effective Infusion Rate to Enhance Postoperative Functions
Current Genomics Diabetes-Induced Alterations in Renal Medullary Microcirculation and Metabolism
Current Diabetes Reviews