Abstract
Granulocyte-macrophage colony stimulating factor (GM-CSF) activity has been linked to pro-inflammatory effects in autoimmune syndromes, such as rheumatoid arthritis. Thus GM-CSF mimetics with antagonist activity might play a therapeutic role in these diseases. The human GM-CSF core structure consists of a four α-helix bundle, and GM-CSF activity is controlled by its binding to a two-subunit receptor. A number of residues located on the B and C helices of GM-CSF are postulated to interact with the alpha chain of the GM-CSF receptor (GM-CSFR). Several approaches have been successfully utilized to develop peptide mimetics of this site, including peptides from the native sequence, a peptide derived from a recombinant antibody (rAb) light chain which mimicked GM-CSF receptor binding activity, and structurally guided de novo design. Analysis of the rAb light chain had suggested mimicry of GM-CSF with residues mostly contributed by the CDR I region. Key residues involved in CDR I peptide / GM-CSFR binding were identified by truncation and alteration of individual residues, while the structural elements required to antagonize the biological action of GM-CSF were separately tested in binding and inhibitory activity assays of multiple cyclic analogues. A peptide designed to retain the loop conformation of the CDR I region of the rAb light c hain competed with GM-CSF for both antibody and receptor binding, but the role of specific residues in antibody versus receptor binding differed markedly. These studies suggest that structural analysis of peptide mimetics can reveal differences in receptor and antibody binding, perhaps including key interactions that impact binding kinetics. Peptide mimetics of other four-helix bundle cytokines are reviewed, including helical and reverse turn mimetics of helical structures. Use of peptide mimetics coupled with structural and kinetic analysis provides a powerful approach to identifying important receptor-ligand interactions, which implications for rational design of novel therapeutics.
Keywords: granulocyte-macrophage colony stimulating factor, gm-csf, gm-csf mimetics, structure-based design
Current Pharmaceutical Design
Title: Structure-based Design of Mimetics for Granulocyte-macrophage Colony Stimulating Factor (GM-CSF)
Volume: 8 Issue: 24
Author(s): Cristina Monfardini, Gabriela Canziani, Carmela Plugariu, Thomas Kieber -Emmons, A. Paul Godillot, Joann Kwah, Joanna Bajgier, Irwin Chaiken and William V. Williams
Affiliation:
Keywords: granulocyte-macrophage colony stimulating factor, gm-csf, gm-csf mimetics, structure-based design
Abstract: Granulocyte-macrophage colony stimulating factor (GM-CSF) activity has been linked to pro-inflammatory effects in autoimmune syndromes, such as rheumatoid arthritis. Thus GM-CSF mimetics with antagonist activity might play a therapeutic role in these diseases. The human GM-CSF core structure consists of a four α-helix bundle, and GM-CSF activity is controlled by its binding to a two-subunit receptor. A number of residues located on the B and C helices of GM-CSF are postulated to interact with the alpha chain of the GM-CSF receptor (GM-CSFR). Several approaches have been successfully utilized to develop peptide mimetics of this site, including peptides from the native sequence, a peptide derived from a recombinant antibody (rAb) light chain which mimicked GM-CSF receptor binding activity, and structurally guided de novo design. Analysis of the rAb light chain had suggested mimicry of GM-CSF with residues mostly contributed by the CDR I region. Key residues involved in CDR I peptide / GM-CSFR binding were identified by truncation and alteration of individual residues, while the structural elements required to antagonize the biological action of GM-CSF were separately tested in binding and inhibitory activity assays of multiple cyclic analogues. A peptide designed to retain the loop conformation of the CDR I region of the rAb light c hain competed with GM-CSF for both antibody and receptor binding, but the role of specific residues in antibody versus receptor binding differed markedly. These studies suggest that structural analysis of peptide mimetics can reveal differences in receptor and antibody binding, perhaps including key interactions that impact binding kinetics. Peptide mimetics of other four-helix bundle cytokines are reviewed, including helical and reverse turn mimetics of helical structures. Use of peptide mimetics coupled with structural and kinetic analysis provides a powerful approach to identifying important receptor-ligand interactions, which implications for rational design of novel therapeutics.
Export Options
About this article
Cite this article as:
Monfardini Cristina, Canziani Gabriela, Plugariu Carmela, Kieber -Emmons Thomas, Godillot Paul A., Kwah Joann, Bajgier Joanna, Chaiken Irwin and Williams V. William, Structure-based Design of Mimetics for Granulocyte-macrophage Colony Stimulating Factor (GM-CSF), Current Pharmaceutical Design 2002; 8 (24) . https://dx.doi.org/10.2174/1381612023393198
DOI https://dx.doi.org/10.2174/1381612023393198 |
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
Blood-based biomarkers in large-scale screening for neurodegenerative diseases
Disease biomarkers are necessary tools that can be employ in several clinical context of use (COU), ranging from the (early) diagnosis, prognosis, prediction, to monitor of disease state and/or drug efficacy. Regarding neurodegenerative diseases, in particular Alzheimer’s disease (AD), a battery of well-validated biomarkers are available, such as cerebrospinal fluid ...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
Diabetes mellitus: advances in diagnosis and treatment driving by precision medicine
Diabetes mellitus (DM) is a chronic degenerative metabolic disease with ever increasing prevalence worldwide which is now an epidemic disease affecting 500 million people worldwide. Insufficient insulin secretion from pancreatic β cells unable to maintain blood glucose homeostasis is the main feature of this disease. Multifactorial and complex nature of ...read more
![](/images/wayfinder.jpg)
- 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
-
Inflammation-Induced Thrombosis: Mechanisms, Disease Associations and Management
Current Pharmaceutical Design Genetic Insights into Sepsis: What have we Learned and How will it Help?
Current Pharmaceutical Design Receptor Guided 3D-QSAR Analysis of Thieno[2,3-b]Pyridine-5- Carbonitrile Inhibitors of Protein Kinase C Theta (PKC-θ )
Combinatorial Chemistry & High Throughput Screening Thalidomide in Multiple Myeloma
Current Pharmaceutical Biotechnology Synthesis, Characterization and Evaluation of 1,3-Bisindolyl-2-Propen-1- One Derivatives as Potent Anti-Breast Cancer Agents
Current Bioactive Compounds Rheumatological Manifestations in Diabetes Mellitus
Current Diabetes Reviews Epigenetic Targets and their Inhibitors in Cancer Therapy
Current Topics in Medicinal Chemistry Nanotechnology: A Novel Approach for Drug Development in Health Care System
Current Nanomaterials Inhibition of microRNA-155 Alleviates Cognitive Impairment in Alzheimer’s Disease and Involvement of Neuroinflammation
Current Alzheimer Research Synthesis and Antitumoral Evaluation of 7-chloro-4-quinolinylhydrazones Derivatives
Medicinal Chemistry Subject Index
Current Drug Targets - Inflammation & Allergy Pulmonary Hypertension and Lung Transplantation
Current Hypertension Reviews The Cyclin-Dependent Kinase Inhibitor p21CDKN1A as a Target of Anti-Cancer Drugs
Current Cancer Drug Targets Inflammaging and Proteases in Abdominal Aortic Aneurysm
Current Vascular Pharmacology HIV: A Raft-Targeting Approach for Prevention and Therapy Using Plant-Derived Compounds (Review)
Current Drug Targets Chromones and their Derivatives as Radical Scavengers: A Remedy for Cell Impairment
Current Topics in Medicinal Chemistry Differential Action of Phytochemicals on Platelet Apoptosis: A Biological Overview
Current Medicinal Chemistry Medicinal and Beneficial Health Applications of Tinospora cordifolia (Guduchi): A Miraculous Herb Countering Various Diseases/Disorders and its Immunomodulatory Effects
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Scintigraphic Imaging of Inflammatory Processes
Medicinal Chemistry Reviews - Online (Discontinued) Progress in Multiple Sclerosis Genetics
Current Genomics