Abstract
Endotoxin, from the outer membrane of Gram-negative bacteria, has been implicated as the etiological agent of a variety of pathologies ranging from relatively mild (fever) to lethal (septic shock, organ failure, and death). While endotoxin (also known as lipopolysaccharide or LPS) is a complex heterogeneous molecule, the toxic portion of LPS (the lipid A portion) is relatively similar across a wide variety of pathogenic strains of bacteria, making this molecule an attractive target for the development of an LPS antagonist. Research over the past fifteen years focused on the design of various lipid A analogs including monosaccharide, acyclic and disaccharide compounds has lead to the development of E5564, an advanced, unique and highly potent LPS antagonist. E5564 is a stable, pure LPS antagonist that is selective against endotoxin-mediated activation of immune cells in vitro and in animal models. In Phase I clinical trials, we have developed an ex vivo endotoxin antagonism assay that has provided results on pharmacodynamic activity of E5564 in addition to the more typical safety and pharmacokinetic evaluations. Results from these assays have been reinforced by analysis of in vivo antagonistic activity using a human endotoxemia model. Results from all of these studies indicate that E5564 is an effective in vivo antagonist of endotoxin, and may prove to be of benefit in a variety of endotoxin-mediated diseases. This review discusses the evolution of synthetic LPS antagonists with emphasis on the SAR and development of E5564 and its precursors.
Keywords: endotoxin, iipopolysaccharide, antagonist, sepsis, septic shock, gram negative, e5564
Current Topics in Medicinal Chemistry
Title: Inhibition of Endotoxin Response by Synthetic TLR4 Antagonists
Volume: 4 Issue: 11
Author(s): Lynn D. Hawkins, William J. Christ and Daniel P. Rossignol
Affiliation:
Keywords: endotoxin, iipopolysaccharide, antagonist, sepsis, septic shock, gram negative, e5564
Abstract: Endotoxin, from the outer membrane of Gram-negative bacteria, has been implicated as the etiological agent of a variety of pathologies ranging from relatively mild (fever) to lethal (septic shock, organ failure, and death). While endotoxin (also known as lipopolysaccharide or LPS) is a complex heterogeneous molecule, the toxic portion of LPS (the lipid A portion) is relatively similar across a wide variety of pathogenic strains of bacteria, making this molecule an attractive target for the development of an LPS antagonist. Research over the past fifteen years focused on the design of various lipid A analogs including monosaccharide, acyclic and disaccharide compounds has lead to the development of E5564, an advanced, unique and highly potent LPS antagonist. E5564 is a stable, pure LPS antagonist that is selective against endotoxin-mediated activation of immune cells in vitro and in animal models. In Phase I clinical trials, we have developed an ex vivo endotoxin antagonism assay that has provided results on pharmacodynamic activity of E5564 in addition to the more typical safety and pharmacokinetic evaluations. Results from these assays have been reinforced by analysis of in vivo antagonistic activity using a human endotoxemia model. Results from all of these studies indicate that E5564 is an effective in vivo antagonist of endotoxin, and may prove to be of benefit in a variety of endotoxin-mediated diseases. This review discusses the evolution of synthetic LPS antagonists with emphasis on the SAR and development of E5564 and its precursors.
Export Options
About this article
Cite this article as:
Hawkins D. Lynn, Christ J. William and Rossignol P. Daniel, Inhibition of Endotoxin Response by Synthetic TLR4 Antagonists, Current Topics in Medicinal Chemistry 2004; 4 (11) . https://dx.doi.org/10.2174/1568026043388123
DOI https://dx.doi.org/10.2174/1568026043388123 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
The Role of Anti-Inflammatory Drugs in Respiratory Diseases - Pirfenidone, Penicillamine, Chloroquine and Chlorambucil
Current Respiratory Medicine Reviews Ghrelin, A Novel Peptide Hormone in the Regulation of Energy Balance and Cardiovascular Function
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Turning Foes to Friends: Knocking Down Diabetes Associated SGLT2 Transporters and Sustaining Life
Current Diabetes Reviews Graphical Abstracts
Inflammation & Allergy - Drug Targets (Discontinued) Metabolic Profile of Flunitrazepam: Clinical and Forensic Toxicological Aspects
Drug Metabolism Letters Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: From Vascular Spasm to Cortical Spreading Depolarizations
Current Neurovascular Research Neurovascular Mechanisms of Hypertension in Pregnancy
Current Neurovascular Research Serum S-100B Protein as A Biochemical Marker of Brain Injury: A Review of Current Concepts
Current Medicinal Chemistry Endothelin-Converting Enzyme Inhibitors
Current Enzyme Inhibition Catheter-directed Thrombolysis <i>versus</i> Systemic Anticoagulation for Submassive Pulmonary Embolism: A Meta-Analysis
Current Cardiology Reviews Tremor and Rigidity in Patients with Parkinson’s Disease: Emphasis on Epidemiology, Pathophysiology and Contributing Factors
CNS & Neurological Disorders - Drug Targets Extrahepatic Targets and Cellular Reactivity of Drug Metabolites
Current Medicinal Chemistry Current Understanding of Polymyxin B Applications in Bacteraemia/ Sepsis Therapy Prevention: Clinical, Pharmaceutical, Structural and Mechanistic Aspects
Anti-Infective Agents in Medicinal Chemistry The Role of Bacterial Lipopolysaccharides as Immune Modulator in Vaccine and Drug Development
Endocrine, Metabolic & Immune Disorders - Drug Targets Nicotine Addiction and Coronary Artery Disease: Impact of Cessation Interventions
Current Pharmaceutical Design Rituximab The First Monoclonal Antibody Approved for the Treatment of Lymphoma
Current Pharmaceutical Biotechnology Glutamate mGlu5-Adenosine A2A-Dopamine D2 Receptor Interactions in the Striatum. Implications for Drug Therapy in Neuro-psychiatric Disorders and Drug Abuse
Current Medicinal Chemistry - Central Nervous System Agents Renal Blood Flow Dynamics in Inbred Rat Strains Provides Insight into Autoregulation
Current Vascular Pharmacology Advances in the Treatment of Neurodegenerative Disorders Employing Nanoparticles
Recent Patents on Drug Delivery & Formulation The Influence of Genetic Variations and Drug Interactions Based on Metabolism of Antidepressants and Anticonvulsants
Current Drug Metabolism