Simultaneous inhibition of key growth pathways in melanoma cells and tumor regression by a designed bidentate constrained helical peptide

Authors

  • Amlanjyoti Dhar,

    1. Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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    • Amlanjyoti Dhar, Shampa Mallick, and Piya Ghosh contributed equally to this work.

  • Shampa Mallick,

    1. Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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    • Amlanjyoti Dhar, Shampa Mallick, and Piya Ghosh contributed equally to this work.

  • Piya Ghosh,

    1. Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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    • Amlanjyoti Dhar, Shampa Mallick, and Piya Ghosh contributed equally to this work.

  • Atanu Maiti,

    1. Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Israr Ahmed,

    1. Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Seemana Bhattacharya,

    1. Division of Cancer Biology and Inflammatory Disorders, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Tapashi Mandal,

    1. Division of Cancer Biology and Inflammatory Disorders, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Asit Manna,

    1. Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Koushik Roy,

    1. Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Sandeep Singh,

    1. National Centre for Cell Science, Pune, Maharashtra, India
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  • Dipak Kumar Nayak,

    1. Division of Infectious Diseases and Immunology, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Paul T. Wilder,

    1. Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD
    2. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD
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  • Joseph Markowitz,

    1. Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD
    2. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD
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  • David Weber,

    1. Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, MD
    2. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD
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  • Mrinal K. Ghosh,

    1. Division of Cancer Biology and Inflammatory Disorders, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Samit Chattopadhyay,

    1. National Centre for Cell Science, Pune, Maharashtra, India
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  • Rajdeep Guha,

    1. Division of Animal House, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Aditya Konar,

    1. Division of Animal House, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Santu Bandyopadhyay,

    1. Division of Cancer Biology and Inflammatory Disorders, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
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  • Siddhartha Roy

    Corresponding author
    1. Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, Kolkata, West Bengal, India
    • Correspondence to: Siddhartha Roy, Division of Structural Biology and Bioinformatics, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India; e-mail: sidroykolkata@gmail.com

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  • This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

ABSTRACT

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 α-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 antiproliferative action 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. At moderate 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. © 2014 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 102: 344–358, 2014.

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