title: Amino Acid-Dependent Attenuation of Toll-like Receptor Signaling by Peptide-Gold Nanoparticle Hybrids.
abstract: Manipulation of immune responsiveness using nanodevices provides a potential approach to treat human diseases. Toll-like receptor (TLR) signaling plays a central role in the pathophysiology of many acute and chronic human inflammatory diseases, and pharmacological regulation of TLR responses is anticipated to be beneficial in many of these inflammatory conditions. Here we describe the discovery of a unique class of peptide-gold nanoparticle hybrids that exhibit a broad inhibitory activity on TLR signaling, inhibiting signaling through TLRs 2, 3, 4, and 5. As exemplified using TLR4, the nanoparticles were found to inhibit both arms of TLR4 signaling cascade triggered by the prototypical ligand, lipopolysaccharide (LPS). Through structure-activity relationship studies, we identified the key chemical components of the hybrids that contribute to their immunomodulatory activity. Specifically, the hydrophobicity and aromatic ring structure of the amino acids on the peptides were essential for modulating TLR4 responses. This work enhances our fundamental understanding of the role of nanoparticle surface chemistry in regulating innate immune signaling, and identifies specific nanoparticle hybrids that may represent a unique class of anti-inflammatory therapeutics for human inflammatory diseases.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Shan-Yu
authors.initials: SY
authors.lastname: Fung
authors.affiliation: ‡Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Xu
authors.forename: Darren P
authors.initials: DP
authors.lastname: Sutherland
authors.forename: Tobias R
authors.initials: TR
authors.lastname: Kollmann
authors.affiliation: ‡Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Turvey
mesh_terms: D024322:Amino Acids, Aromatic / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006046:Gold; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000737:chemistry*; D053768:Metal Nanoparticles / Q000737:chemistry*; D058726:Nanoconjugates / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D024322:Amino Acids, Aromatic; D007155:Immunologic Factors; D058726:Nanoconjugates; D010455:Peptides; D051193:Toll-Like Receptors; D006046:Gold
keywords: IRF3; NF-κB; Toll-like receptor signaling; amino acids; gold nanoparticles; immune modulation; peptides; surface chemistry