Topomimetics of Amphipathic -Sheet and Helix-Forming Bactericidal Peptides Neutralize Lipopolysaccharide Endotoxins
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- 作者：Xuemei Chen ; Ruud P. M. Dings ; Irina Nesmelova ; Stefan Debbert ; Judith R. Haseman ; Jacques Maxwell ; Thomas R. Hoye ; Kevin H. Mayo
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：December 28, 2006
- 年：2006
- 卷：49
- 期：26
- 页码：7754 - 7765
- 全文大小：422K
- 年卷期：v.49,no.26(December 28, 2006)
- ISSN：1520-4804
文摘
Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophagesto produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bindto and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection.Previously, we reported the design of antibacterial helix peptide SC4 and 
-sheet-forming pep peptidesthat neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralizeLPS rested in the common denominator of positively charged amphipathic structure. Here, we describe thedesign and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the foldedconformations of these peptides in their molecular dimensions, amphipathic surface topology, andcompositional properties. From a small library of topomimetics, we identified several compounds thatneutralize LPS in the 10-8 M range, making them as effective as bactericidal/permeability increasing proteinand polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics areshown to be at least partially protective against challenges of LPS from different bacterial species. NMRstudies provide mechanistic insight by suggesting the site of molecular interaction between topomimeticsand the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions.This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.
-sheet-forming pep peptidesthat neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralizeLPS rested in the common denominator of positively charged amphipathic structure. Here, we describe thedesign and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the foldedconformations of these peptides in their molecular dimensions, amphipathic surface topology, andcompositional properties. From a small library of topomimetics, we identified several compounds thatneutralize LPS in the 10-8 M range, making them as effective as bactericidal/permeability increasing proteinand polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics areshown to be at least partially protective against challenges of LPS from different bacterial species. NMRstudies provide mechanistic insight by suggesting the site of molecular interaction between topomimeticsand the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions.This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.