Site-specific effect of polar functional group-modification in lipids of TLR2 ligands for modulating the ligand immunostimulatory activity

Yohei Arai, Shinsuke Inuki, Yukari Fujimoto

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Toll-like receptor 2 (TLR2), a member of the TLR innate immune receptor family, recognizes lipoproteins from bacteria and modulates the immune response by inducing the expression of various cytokines. TLR2 has a large hydrophobic pocket that recognizes long fatty acyl groups on TLR2 ligands. However, few studies have focused on the property of the hydrophobic TLR2 pocket. Based on the X-ray crystal structure of TLR2, small polar regions were found in the hydrophobic TLR2 pocket. Interactions between the polar residues and ligands were explored here by designing and synthesizing a Pam2CSK4 derivative of the TLR2 ligands, containing an amide group within the lipid moiety. We evaluated the binding affinities and immunomodulatory activities of these ligands. Results suggested that the amide groups in the lipid chain interacted with the polar residues in the hydrophobic lipid-binding pocket of TLR2.

Original languageEnglish
Pages (from-to)1638-1641
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number9
DOIs
Publication statusPublished - 2018 May 15

Keywords

  • Lipopeptide
  • PamCSK
  • Structure–activity relationship
  • Toll-like receptor 2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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