Abstract
Biological activity and clinical efficacy of a therapeutic protein are contingent upon the structural stability, bioavailability, and clearance rates of the protein. In this review, we examine the class of 4-helical bundle cytokines for common stability properties that may affect biological structure and efficacy. Three critical stability features that are hallmarks of this class of cytokines are the pH dependence of structural stability, the presence of folding intermediates, and the population of aggregation intermediates. We hypothesize that certain cytokines have increased stability in acid to enable receptor-mediated clearance, and that reengineering local endocytic trafficking can result in dramatic improvements in global serum half-life and therapeutic efficacy. The common feature of folding and aggregation intermediates has implications on kinetic folding pathways, membrane permeability, solubility, and precipitation properties that are critical for commercial production, formulation, and delivery. Understanding the structural stability properties of this class of cytokines may help elucidate new approaches to improving therapeutic efficacy.
Keywords: circular dichroism, fluorescence, hplc, clearance, erythropoietin
Current Pharmaceutical Design
Title: Common Structural Stability Properties of 4-Helical Bundle Cytokines: Possible Physiological and Pharmaceutical Consequences
Volume: 10 Issue: 31
Author(s): Margaret Speed Ricci and David N. Brems
Affiliation:
Keywords: circular dichroism, fluorescence, hplc, clearance, erythropoietin
Abstract: Biological activity and clinical efficacy of a therapeutic protein are contingent upon the structural stability, bioavailability, and clearance rates of the protein. In this review, we examine the class of 4-helical bundle cytokines for common stability properties that may affect biological structure and efficacy. Three critical stability features that are hallmarks of this class of cytokines are the pH dependence of structural stability, the presence of folding intermediates, and the population of aggregation intermediates. We hypothesize that certain cytokines have increased stability in acid to enable receptor-mediated clearance, and that reengineering local endocytic trafficking can result in dramatic improvements in global serum half-life and therapeutic efficacy. The common feature of folding and aggregation intermediates has implications on kinetic folding pathways, membrane permeability, solubility, and precipitation properties that are critical for commercial production, formulation, and delivery. Understanding the structural stability properties of this class of cytokines may help elucidate new approaches to improving therapeutic efficacy.
Export Options
About this article
Cite this article as:
Ricci Speed Margaret and Brems N. David, Common Structural Stability Properties of 4-Helical Bundle Cytokines: Possible Physiological and Pharmaceutical Consequences, Current Pharmaceutical Design 2004; 10 (31) . https://dx.doi.org/10.2174/1381612043382611
DOI https://dx.doi.org/10.2174/1381612043382611 |
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
-
Neurotoxicity and Side-Effects of Highly Active Antiretroviral Therapy [HAART] on the Central and Peripheral Nerve System
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Ivabradine for Treatment of Coronary Artery Disease: From Last Chance Resort to Mainstem of a Reasoned Therapy
Cardiovascular & Hematological Agents in Medicinal Chemistry MicroRNAs and Diabetes Mellitus Type 1
Current Diabetes Reviews Blood Platelet Reactivity and its Pharmacological Modulation in (People with) Diabetes Mellitus
Current Pharmaceutical Design Impact of Angiotensin Converting Enzyme Inhibitors/Angiotensin Receptors Blockers on Mortality in Acute Heart Failure Patients with Left Ventricular Systolic Dysfunction in the Middle East: Observations from the Gulf Acute Heart Failure Registry (Gulf CARE)
Current Vascular Pharmacology Clinical Features and Disease Damage Risk Factors in an Egyptian SLE Cohort: A Multicenter Study
Current Rheumatology Reviews Erythropoietin: New Horizon in Cardiovascular Medicine
Recent Patents on Cardiovascular Drug Discovery Impact of Diabetes on Cardiac and Vascular Disease: Role of Calcium Signaling
Current Medicinal Chemistry Brachial-Ankle Pulse Wave Velocity in the Measurement of Arterial Stiffness: Recent Evidence and Clinical Applications
Current Hypertension Reviews The Role of Renin Angiotensin System Blockade in the Treatment of Atrial Fibrillation
Current Drug Targets - Cardiovascular & Hematological Disorders Patent Selections:
Recent Patents on Regenerative Medicine Therapeutic Targets to Raise HDL in Patients at Risk or with Coronary Artery Disease
Current Vascular Pharmacology Interplay of Breast Cancer Resistance Protein (BCRP) and Metabolizing Enzymes
Current Drug Metabolism The Role of Statins in the Management of Nonalcoholic Fatty Liver Disease
Current Pharmaceutical Design Effect of Solvents, Drug/Polymer Ratio and Surfactant Concentration on In Vitro Characteristic of Repaglinide Loaded Poly (Meth) Acrylate Nanoparticles
Micro and Nanosystems Development of Insulin Resistance During Aging: Involvement of Central Processes and Role of Adipokines
Current Protein & Peptide Science Formation Mechanism of Insulin Fibrils and Structural Aspects of the Insulin Fibrillation Process
Current Protein & Peptide Science Diabetes Mellitus-Cell Transplantation and Gene Therapy Approaches.
Current Molecular Medicine Resveratrol and Analogues: A Review of Antioxidant Activity and Applications to Human Health
Recent Patents on Food, Nutrition & Agriculture Beneficial Effects of Statins on Endothelial Dysfunction and Vascular Stiffness
Current Vascular Pharmacology