Abstract
Lipopolysaccharide (LPS), the glycolipid of the outer membrane of Gram-negative bacteria, is critically involved in health and diseases. LPS facilitates the survival of pathogens by imposing a permeability barrier against antibiotics and antimicrobial peptides. LPS, also termed as endotoxin, functions as a potent inducer of innate immunity. Interception of endotoxin in systemic circulation by immune cells e.g. macrophages is essential to mount surveillance against invading microbes. However, a hyper-activated immune response may lead to the overwhelming production of tissue damaging cytokines TNF-α, IL-1, IL-6 and free radicals that may cause multiple organ failures or septic shock syndromes. The sepsis or septic shock is the major cause of mortality; 120,000 deaths/year occur in the United States alone, in the intensive care units. To-date, no therapeutic is available to combat sepsis mediated lethality. Furthermore, bacterial resistance against commonly used antibiotics has been increasing at an alarming rate necessitating a search for antibacterial agents with novel mode of actions. LPS could be a valid drug target for the development of antiendotoxic and antimicrobial compounds. In this article, recent advances in structural basis of LPS recognition by its receptor proteins and mode of actions of antimicrobial peptides defensins and cathelicidins are reviewed. Our research has identified, through de novo design, antimicrobial and endotoxin interacting β-boomerang peptides. Structure-activity correlations (SAR) of these peptides have been discussed, highlighting future design to achieve potent LPS neutralizing molecules.
Keywords: Lipopolysaccharide, antimicrobial peptide, de novo designed peptide, endotoxin, sepsis, NMR, tr-NOE, STD-NMR
Current Medicinal Chemistry
Title: De novo Designed Lipopolysaccharide Binding Peptides: Structure Based Development of Antiendotoxic and Antimicrobial Drugs
Volume: 17 Issue: 27
Author(s): S. Bhattacharjya
Affiliation:
Keywords: Lipopolysaccharide, antimicrobial peptide, de novo designed peptide, endotoxin, sepsis, NMR, tr-NOE, STD-NMR
Abstract: Lipopolysaccharide (LPS), the glycolipid of the outer membrane of Gram-negative bacteria, is critically involved in health and diseases. LPS facilitates the survival of pathogens by imposing a permeability barrier against antibiotics and antimicrobial peptides. LPS, also termed as endotoxin, functions as a potent inducer of innate immunity. Interception of endotoxin in systemic circulation by immune cells e.g. macrophages is essential to mount surveillance against invading microbes. However, a hyper-activated immune response may lead to the overwhelming production of tissue damaging cytokines TNF-α, IL-1, IL-6 and free radicals that may cause multiple organ failures or septic shock syndromes. The sepsis or septic shock is the major cause of mortality; 120,000 deaths/year occur in the United States alone, in the intensive care units. To-date, no therapeutic is available to combat sepsis mediated lethality. Furthermore, bacterial resistance against commonly used antibiotics has been increasing at an alarming rate necessitating a search for antibacterial agents with novel mode of actions. LPS could be a valid drug target for the development of antiendotoxic and antimicrobial compounds. In this article, recent advances in structural basis of LPS recognition by its receptor proteins and mode of actions of antimicrobial peptides defensins and cathelicidins are reviewed. Our research has identified, through de novo design, antimicrobial and endotoxin interacting β-boomerang peptides. Structure-activity correlations (SAR) of these peptides have been discussed, highlighting future design to achieve potent LPS neutralizing molecules.
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Cite this article as:
Bhattacharjya S., De novo Designed Lipopolysaccharide Binding Peptides: Structure Based Development of Antiendotoxic and Antimicrobial Drugs, Current Medicinal Chemistry 2010; 17 (27) . https://dx.doi.org/10.2174/092986710791959756
DOI https://dx.doi.org/10.2174/092986710791959756 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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