Abstract
Lipopolysaccharides (LPS), otherwise termed endotoxins, are an integral part of the outer leaflet of the outermembrane of Gram-negative bacteria. Lipopolysaccharides play a pivotal role in the pathogenesis of Septic Shock, a major cause of mortality in the critically ill patient, worldwide. The sequestration of circulatory endotoxin may be a viable therapeutic strategy for the prophylaxis and treatment of Gram-negative sepsis. We have earlier shown that the pharmacophore necessary for small molecules to bind LPS involves two protonatable cationic functions separated by about 15 Å, permitting the simultaneous interaction with the negatively charged phosphates on lipid A, the toxically active center of endotoxin. In this report, screening of a multi-thousand membered polyamine library through the combined use of computational and bioassay-guided screens resulted in the discovery of two novel classes of LPS-binding agents. These are represented by the 1) spermine sulfonamides and 2) C-aryl-substituted spermine analogs. We present the selection approach, screening results, computational multivariate analyses and initial structure-activity relationship evaluation herein.
Keywords: Endotoxin, lipopolysaccharide, sepsis, shock, fluorescence, high-throughput screening
Combinatorial Chemistry & High Throughput Screening
Title: Anti-Endotoxin Agents. 3. Rapid Identification of High-Affinity Lipopolysaccharide-Binding Compounds in a Substituted Polyamine Library
Volume: 9 Issue: 1
Author(s): Stewart J. Wood, Kelly A. Miller, Gerald H. Lushington, Mark R. Burns and Sunil A. David
Affiliation:
Keywords: Endotoxin, lipopolysaccharide, sepsis, shock, fluorescence, high-throughput screening
Abstract: Lipopolysaccharides (LPS), otherwise termed endotoxins, are an integral part of the outer leaflet of the outermembrane of Gram-negative bacteria. Lipopolysaccharides play a pivotal role in the pathogenesis of Septic Shock, a major cause of mortality in the critically ill patient, worldwide. The sequestration of circulatory endotoxin may be a viable therapeutic strategy for the prophylaxis and treatment of Gram-negative sepsis. We have earlier shown that the pharmacophore necessary for small molecules to bind LPS involves two protonatable cationic functions separated by about 15 Å, permitting the simultaneous interaction with the negatively charged phosphates on lipid A, the toxically active center of endotoxin. In this report, screening of a multi-thousand membered polyamine library through the combined use of computational and bioassay-guided screens resulted in the discovery of two novel classes of LPS-binding agents. These are represented by the 1) spermine sulfonamides and 2) C-aryl-substituted spermine analogs. We present the selection approach, screening results, computational multivariate analyses and initial structure-activity relationship evaluation herein.
Export Options
About this article
Cite this article as:
Wood J. Stewart, Miller A. Kelly, Lushington H. Gerald, Burns R. Mark and David A. Sunil, Anti-Endotoxin Agents. 3. Rapid Identification of High-Affinity Lipopolysaccharide-Binding Compounds in a Substituted Polyamine Library, Combinatorial Chemistry & High Throughput Screening 2006; 9 (1) . https://dx.doi.org/10.2174/138620706775213903
DOI https://dx.doi.org/10.2174/138620706775213903 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
Call for Papers in Thematic Issues
Artificial Intelligence Methods for Biomedical, Biochemical and Bioinformatics Problems
Recently, a large number of technologies based on artificial intelligence have been developed and applied to solve a diverse range of problems in the areas of biomedical, biochemical and bioinformatics problems. By utilizing powerful computing resources and massive amounts of data, methods based on artificial intelligence can significantly improve the ...read more
Eco-friendly Agents for Biological Control of Pathogenic Diseases
The discovery of an alternative biological approach to disease management includes work on medicinal products derived from natural sources as a starting point for the development of eco-friendly agents for these diseases and the injuries they cause, as well as reducing human contact with hazardous chemicals and their residues. We ...read more
Emerging trends in diseases mechanisms, noble drug targets and therapeutic strategies: focus on immunological and inflammatory disorders
Recently infectious and inflammatory diseases have been a key concern worldwide due to tremendous morbidity and mortality world Wide. Recent, nCOVID-9 pandemic is a good example for the emerging infectious disease outbreak. The world is facing many emerging and re-emerging diseases out breaks at present however, there is huge lack ...read more
Exploring Spectral Graph Theory in Combinatorial Chemistry
Scope of the Thematic Issue: Combinatorial chemistry involves the synthesis and analysis of a large number of diverse compounds simultaneously. Traditional methods rely on brute force experimentation, which can be time-consuming and resource-intensive. Spectral Graph Theory, a branch of mathematics dealing with the properties of graphs in relation to the ...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
Related Articles
-
Pharmacological Uses of the Plants Belonging to the Genus <i>Commiphora</i>
Cardiovascular & Hematological Agents in Medicinal Chemistry Uteroplacental Circulation and Fetal Vascular Function and Development
Current Vascular Pharmacology Understanding the Cardiovascular Actions of Soy Isoflavones: Potential Novel Targets for Antihypertensive Drug Development
Cardiovascular & Hematological Disorders-Drug Targets Role of Iron Deficiency and Overload in the Pathogenesis of Diabetes and Diabetic Complications
Current Medicinal Chemistry Simple and Efficient Synthesis of Novel bis-Betti Bases via a One-Pot Pseudo-Five-Component Reaction
Letters in Organic Chemistry Lactic Acidosis, Hypotension, and Sensorineural Hearing Loss Following Intentional Metformin Overdose
Current Drug Safety C-type Natriuretic Peptide (CNP): Cardiovascular Roles and Potential as a Therapeutic Target
Current Pharmaceutical Design Current Status of Leukemia Cytotherapy - Exploitation with Immune Cells
Current Stem Cell Research & Therapy AMPA Glutamate Receptors and Neuropathic Pain
Mini-Reviews in Medicinal Chemistry From Antidepressant Drugs to Beta-Mimetics: Preclinical Insights on Potential New Treatments for Neuropathic Pain
Recent Patents on CNS Drug Discovery (Discontinued) The Use of TNF Family Ligands and Receptors and Agents which Modify their Interaction as Therapeutic Agents
Current Drug Targets Tailored Angiogenesis Inhibition in Cancer Therapy: Respecting the Heart to Improve the Net Outcome
Current Signal Transduction Therapy Inhibition of Histone Deacetylases: A Pharmacological Approach to the Treatment of Non-Cancer Disorders
Current Topics in Medicinal Chemistry Update on the Cardiac Safety of Moxifloxacin
Current Drug Safety Baicalein-Phospholipid Complex: A Novel Drug Delivery Technology for Phytotherapeutics
Current Drug Discovery Technologies Childhood Solitary Cutaneous Mastocytoma: Clinical Manifestations, Diagnosis, Evaluation, and Management
Current Pediatric Reviews Pharmacological and Clinical Applications of Natriuretic Peptides: Accepted Knowledges or Changing Views?
Current Pharmaceutical Analysis Targeting the Immune System in Cancer
Current Pharmaceutical Biotechnology The Renin-Angiotensin System in the Mammalian Central Nervous System
Current Protein & Peptide Science New Mucoadhesive Polymeric Film for Ophthalmic Administration of Acetazolamide
Recent Patents on Drug Delivery & Formulation