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A novel small-molecule PPI inhibitor targeting integrin alpha(v)beta(3)-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice

Title
A novel small-molecule PPI inhibitor targeting integrin alpha(v)beta(3)-osteopontin interface blocks bone resorption in vitro and prevents bone loss in mice
Authors
Park, DooriPark, Chan-WonChoi, YoungJinLin, JingjingSeo, Dong-HyunKim, Han-SungLee, Soo YoungKang, In-Cheol
Ewha Authors
이수영
SCOPUS Author ID
이수영scopus
Issue Date
2016
Journal Title
BIOMATERIALS
ISSN
0142-9612JCR Link1878-5905JCR Link
Citation
vol. 98, pp. 131 - 142
Keywords
Small-molecule PPI inhibitorProteoChipIn silico molecular docking simulationOsteoclast inhibitionBone resorptionIntegrin alpha(v)beta(3)-OPN interface
Publisher
ELSEVIER SCI LTD
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Small molecule-inhibition targeting protein-protein interaction (PPI) is now recognized as an emerging and challenging area in drug design. We developed a novel interactive drug discovery methodology known as Protein Chip technology (ProteoChip) as a cutting-edge PPI assay system applicable for unique PPI-targeting therapeutics integrated with computer-aided drug design (CADD). Here, we describe a novel small molecular PPI inhibitor, IPS-02001, which the blocks integrin alpha(v)beta(3)-osteopontin interface a novel PPI inhibitor identified by the interactive methodology of both ProteoChip- and CADD-based PPI assay. IPS-02001 (6,7-Dichloro-2,3,5,8-tetrahydroxy-1,4-naphthoquinone) was screened from different compound libraries (InterBioScreen, Commercial libraries) using an in silica structure-based molecular docking simulation method and a protein chip-based protein-protein interaction assay system. Additionally, integrin alpha(v)beta(3), an adhesion receptor expressed in osteoclasts (OCs), was implicated in the regulation of OC function via regulation of the cytoskeletal organization of OCs. IPS-02001 blocked OC maturation from murine bone marrow-derived macrophages, as well as the resorptive function of OCs. Moreover, treatment with IPS-02001 impaired downstream signaling of integrin alpha(v)beta(3) linked to Pyk2, c-Src, PLC gamma 2, and Vav3 and disrupted the actin cytoskeleton in mature OCs. Furthermore, IPS-02001 blocked RANKL-induced bone destruction by reducing the number of OCs and protected against ovariectomy-induced bone loss in mice. Thus, IPS-02001 may represent a promising new class of anti-resorptive drugs for treatment of bone diseases associated with increased OC function. (C) 2016 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.biomaterials.2016.05.007
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자연과학대학 > 생명과학전공 > Journal papers
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