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Bang J.-Y.,Hoseo University | Kim E.-Y.,Hoseo University | Kang D.-K.,Imperial College London | Chang S.-I.,Chungbuk National University | And 3 more authors.
Molecular and Cellular Proteomics | Year: 2011

P11, a novel peptide ligand containing a PDZ-binding motif (Ser-Asp-Val) with high affinity to integrin α vβ 3 was identified from a hexapeptide library (PS-SPCL) using a protein microarray chip-based screening system. Here, we investigated the inhibitory mechanism of P11 (HSD-VHK) on tumor-induced angiogenesis via a pharmacoproteomic approach. P11 was rapidly internalized by , human umbilical vein endothelial cells (HUVECs) via an integrin α vβ 3-mediated event. Caveolin and clathrin appeared to be involved in the P11 uptake process. The cell-penetrating P11 resulted in suppression of bFGF-induced HUVEC proliferation in a dose-dependent manner. Phosphorylation of extracellular-signal regulated kinase (ERK1/2) and mitogen-activated protein kinase kinase (MEK) in bFGF-stimulated HUVECs was inhibited by cell-permeable P11. Proteomic analysis via antibody microarray showed upregulation of p53 in P11-treated HUVECs, resulting in induction of apoptosis via activation of caspases-3, -8, and -9. Several lines of experimental evidence strongly suggest that the molecular mechanism of P11, a novel antiangiogenic agent, inhibits bFGF-induced HUVEC proliferation via mitogen-activated protein kinase kinase and extracellular-signal regulated kinase inhibition as well as p53-mediated apoptosis related with activation of caspases. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Choi Y.,BioChip Research Center | Kim E.,BioChip Research Center | Kim E.,Innopharmascreen Inc. | Lee Y.,Proteogen Inc. | And 4 more authors.
Proteomics | Year: 2010

A functional proteomic technology using protein chip and molecular simulation was used to demonstrate a novel biomolecular interaction between P11, a peptide containing the Ser-Asp-Val (SDV) sequence and integrin αvβ3. P11 (HSDVHK) is a novel antagonistic peptide of integrin αvβ3 screened from hexapeptide library through protein chip system. An in silico docking study and competitive protein chip assay revealed that the SDV sequence of P11 is able to create a stable inhibitory complex onto the vitronectin-binding site of integrin αvβ3. The Arg-Gly-Asp (RGD)-binding site recognition by P11 was site specific because the P11 was inactive for the complex formation of a denatured form of integrin-vitronectin. P11 showed a strong antagonism against αvβ3-GRGDSP interaction with an IC50 value of 25.7±73.34 nM, whereas the value of GRGDSP peptide was 1968.73±444.32 nM. The binding-free energies calculated from the docking simulations for each P11 and RGD peptide were -3.99 and -3.10 kcal/mol, respectively. The free energy difference between P11 and RGD corresponds to approximately a 4.5-fold lower Ki value for the P11 than the RGD peptide. The binding orientation of the docked P11 was similar to the crystal structure of the RGD in αvβ3. The analyzed docked poses suggest that a divalent metal-ion coordination was a common driving force for the formation of both SDV/αvβ3 and RGD/αvβ3 complexes. This is the first report on the specific recognition of the RGD-binding site of αvβ3 by a non-RGD containing peptide using a computer-assisted proteomic approach. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Min D.,Yonsei University | Han M.H.,Proteogen Inc. | Lee S.,Proteogen Inc. | Jung M.,Yonsei University
Chemical and Pharmaceutical Bulletin | Year: 2015

The first total synthesis for large-scale production and anticancer activity of novel aminophenylpyridinium-5-(hydroxybenzoyl)hydrazonomethyl-2-oxothiazol-3-ide (PBHT) (1) and its derivatives are reported. The chemical structure of PBHT was unambiguously determined by utilization of the two-dimensional nuclear Overhauser effect (NOE) technique. The anticancer activity against human colon adenocarcinoma (HCT15) cells of all synthesized compounds was approximately four-fold greater than that of 5-fluorouracil, with IC50 values ranging from 10.1 to 14.2 μM. The three structural determinants of hydroxybenzoyl, hydrazinylidene, and pyridinium oxothiazole in the synthesized compounds could be indispensable for exhibiting anticancer activity. © 2015 The Pharmaceutical Society of Japan.

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