title: Topomimetics of amphipathic beta-sheet and helix-forming bactericidal peptides neutralize lipopolysaccharide endotoxins.
abstract: 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 beta-sheet-forming betapep 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Chen
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.forename: Irina
authors.initials: I
authors.lastname: Nesmelova
authors.forename: Stefan
authors.initials: S
authors.lastname: Debbert
authors.forename: Judith R
authors.initials: JR
authors.lastname: Haseman
authors.forename: Jacques
authors.initials: J
authors.lastname: Maxwell
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hoye
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000494:pharmacology; D047250:Calixarenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019446:Endotoxemia / Q000188:drug therapy; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006737:Horseshoe Crabs / Q000737:chemistry; D008050:Lipid A / Q000737:chemistry; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D009500:Neutralization Tests; D011112:Polymyxin B / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D004731:Endotoxins; D008050:Lipid A; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C021623:bactericidal permeability increasing protein; C025357:endotoxin binding proteins; D047250:Calixarenes; D011112:Polymyxin B