Topomimetics of amphipathic β-sheet and helix-forming bactericidal peptides neutralize lipopolysaccharide endotoxins

Xuemei Chen, Ruud P.M. Dings, Irina Nesmelova, Stefan Debbert, Judith R. Haseman, Jacques Maxwell, Thomas R. Hoye, Kevin H. Mayo

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to 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 β-sheet-forming βpep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10-8 M range, making them as effective as bactericidal/permeability increasing protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and 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.

Original languageEnglish (US)
Pages (from-to)7754-7765
Number of pages12
JournalJournal of medicinal chemistry
Issue number26
StatePublished - Dec 28 2006


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