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Identification of inhibitors against interaction between pro-inflammatory sPLA2-IIA protein and integrin αvβ3.

Authors
  • L, Ye
  • T, Dickerson
  • H, Kaur
  • Yk, Takada
  • M, Fujita
  • R, Liu
  • Jm, Knapp
  • Ks, Lam
  • Ne, Schore
  • Mj, Kurth
  • Yoshikazu Takada
Type
Published Article
Journal
Bioorganic & Medicinal Chemistry Letters
Publisher
Elsevier
Volume
23
Issue
1
Pages
340–340
Identifiers
DOI: 10.1016/j.bmcl.2012.10.080
Source
Takada Lab - UC Davis dermatology-ucdavis
License
Unknown

Abstract

Increased concentrations of secreted phospholipase A2 type IIA (sPLA2-IIA), have been found in the synovial fluid of patients with rheumatoid arthritis. It has been shown that sPLA2-IIA specifically binds to integrin αvβ3, and initiates a signaling pathway that leads to cell proliferation and inflammation. Therefore, the interaction between integrin and sPLA2-IIA could be a potential therapeutic target for the treatment of proliferation or inflammation-related diseases. Two one-bead-one-compound peptide libraries were constructed and screened, and seven target hits were identified. Herein we report the identification, synthesis, and biological testing of two pyrazolylthiazole-tethered peptide hits and their analogs. Biological assays showed that these compounds were able to suppress the sPLA2-IIA-integrin interaction and sPLA2-IIA-induced migration of monocytic cells and that the blockade of the sPLA2-IIA-integrin binding was specific to sPLA2-IIA and not to the integrin.

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