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
-
Review of Ocular Drug Delivery
Current Drug Delivery Dipeptidyl-peptidase 4 Inhibition: Linking Metabolic Control to Cardiovascular Protection
Current Pharmaceutical Design Action Mechanism of Antihistamines and the New Antihistamines
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Medical Treatment of Hirsutism in Women
Current Medicinal Chemistry Nociceptin/Orphanin FQ Peptide Receptor as a Therapeutic Target for Obesity
Mini-Reviews in Medicinal Chemistry Mechanisms of Interferon Mediated Anti-Viral Resistance
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Relevance of the Vascular Effects of Insulin in the Rationale of its Therapeutical Use
Cardiovascular & Hematological Disorders-Drug Targets The Clinical Pathway for Hypertensive Patient of Local Health Unit, Hospitals and General Practitioners, the Milan Experience
Reviews on Recent Clinical Trials Pain-Relief Medication and Risk of Fractures
Current Drug Safety Targeting Malignancies with Disulfiram (Antabuse): Multidrug Resistance, Angiogenesis, and Proteasome
Current Cancer Drug Targets Pharmacological Potential of Exercise and RAS Vasoactive Peptides for Prevention of Diseases
Current Protein & Peptide Science Addiction Liability of Pharmacotherapeutic Interventions in Obesity
Current Pharmaceutical Design Relaxin as a Cardiovascular Drug: A Promise Kept
Current Drug Safety Usefulness of Real-Time PCR for the Diagnosis of Sepsis in ICU-Acquired Infections
Infectious Disorders - Drug Targets Plasma Substitutes Therapy in Pediatrics
Current Drug Targets Neuroprotection by Diazoxide in Animal Models for Cerebrovascular Disorders
Vascular Disease Prevention (Discontinued) Acute Decompensated Heart Failure Update
Current Cardiology Reviews Irbesartan and Hydrochlorothiazide Association in the Treatment of Hypertension
Current Vascular Pharmacology Autonomic Nervous System Dysfunction in Sjogrens Syndrome
Current Rheumatology Reviews Hypertension in Patients with Severe Aortic Stenosis: Emphasis on Antihypertensive Treatment and the Risk of Syncope
Current Hypertension Reviews