Papaverine identified as an inhibitor of high mobility group box 1/receptor for advanced glycation end-products interaction suppresses high mobility group box 1-mediated inflammatory responses.
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| Abstract |
The interaction of high mobility group box 1 (HMGB1), which is secreted from immune and dying cells during cellular infection and injury, and receptor for advanced glycation end-products (RAGE) appears to be critical for acute and chronic inflammatory disorders. Here we designed a unique cyclic β-hairpin peptide (Pepb2), which mimics the predicted RAGE-binding domain of HMGB1. Pepb2 competitively inhibited HMGB1/RAGE interaction. We then identified papaverine as a Pepb2 mimetic by in silico 3D-structural similarity screening from the DrugBank library. Papaverine was found to directly inhibit HMGB1/RAGE interaction. It also suppressed the HMGB1-mediated production of pro-inflammatory cytokines, IL-6 and TNF-α, in mouse macrophage-like RAW264.7 cells and bone marrow-derived macrophages. In addition, papaverine attenuated mortality in cecal ligation puncture-induced sepsis model mice. Taken together, these findings indicate that papaverine could become a useful therapeutic against HMGB1/RAGE-mediated sepsis and other inflammatory diseases.
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| Authors | Kenya Tamada, Shingo Nakajima, Natsumi Ogawa, Mana Inada, Hiroyuki Shibasaki, Akira Sato, Ryoko Takasawa, Atsushi Yoshimori, Yusuke Suzuki, Nobuo Watanabe, Takahiro Oyama, Hideaki Abe, Shigeaki Inoue, Takehiko Abe, Takehiko Yokomizo, S Tanuma |
| Journal | Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 511 Issue 3 Pg. 665-670 (04 09 2019) ISSN: 1090-2104 [Electronic] United States |
| PMID | 30826057 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2019 Elsevier Inc. All rights reserved. |
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