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Simultaneous Inhibition of Key Growth Pathways in Melanoma Cells and Tumor Regression by a Designed Bidentate Constrained Helical Peptide

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Title Simultaneous Inhibition of Key Growth Pathways in Melanoma Cells and Tumor Regression by a Designed Bidentate Constrained Helical Peptide
 
Creator Dhar, Amlanjyoti
Mallick, Shampa
Ghosh, Piya
Maiti, Atanu
Ahmed, Israr
Bhattacharya, Seemana
Mandal, Tapashi
Manna, Asit
Roy, Koushik
Singh, Sandeep
Nayak, Dipak Kumar
Wilder, Paul T
Markowitz, Joseph
Weber, David
Ghosh, Mrinal K.
Chattopadhyay, Samit
Guha, Rajdeep
Bandyopadhyay, Santu
Roy, Siddhartha
 
Subject Cancer Biology and Inflammatory Disorder Division
Infectious Diseases and Immunology
Structural Biology & Bioinformatics
Animal House
 
Description Protein–protein interactions are part of a large number
of signaling networks and potential targets for drug development. However, discovering molecules that can specifically inhibit such interactions is a major challenge.
S100B, a calcium-regulated protein, plays a crucial role
in the proliferation of melanoma cells through protein–
protein interactions. In this article, we report the design
and development of a bidentate conformationally constrained
peptide against dimeric S100B based on a natural tight-binding peptide, TRTK-12. The helical conformation of the peptide was constrained by the substitution of a-amino isobutyric acid—an amino acid having high helical propensity—in positions which do not interact with S100B. A branched bidentate version of the peptide was bound to S100B tightly with a dissociation constant of 8 nM. When conjugated to a cell-penetrating peptide, it caused growth inhibition and rapid apoptosis in melanoma cells. The molecule exerts antiproliferativeaction through simultaneous inhibition of key growth pathways, including reactivation of wild-type p53 and inhibition of Akt and STAT3 phosphorylation. The apoptosis induced by the bidentate constrained helix is caused by direct migration of p53 to mitochondria. Atmoderate intravenous dose, the peptide completely inhibits melanoma growth in a mouse model without any significant observable toxicity. The specificity was shown by lack of ability of a double mutant peptide to cause tumor regression at the same dose level. The methodology described here for direct protein–protein interaction inhibition may be effective for rapid development of inhibitors against relatively weak protein–protein interactions for de novo drug development. VC 2014 Wiley Periodicals,
Inc. Biopolymers (Pept Sci) 102: 344–358, 2014
 
Publisher John Wiley & Sons
 
Date 2014
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2166/1/BIOPOLYMERS__V_102__(_4)_344%2D358;2014[86].pdf
Dhar, Amlanjyoti and Mallick, Shampa and Ghosh, Piya and Maiti, Atanu and Ahmed, Israr and Bhattacharya, Seemana and Mandal, Tapashi and Manna, Asit and Roy, Koushik and Singh, Sandeep and Nayak, Dipak Kumar and Wilder, Paul T and Markowitz, Joseph and Weber, David and Ghosh, Mrinal K. and Chattopadhyay, Samit and Guha, Rajdeep and Bandyopadhyay, Santu and Roy, Siddhartha (2014) Simultaneous Inhibition of Key Growth Pathways in Melanoma Cells and Tumor Regression by a Designed Bidentate Constrained Helical Peptide. Biopolymers: Peptide Science, 102 (4). pp. 344-358. ISSN 0006-3525
 
Relation http://dx.doi.org/10.1002/bip.22505
http://www.eprints.iicb.res.in/2166/