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

Amlanjyoti Dhar, Shampa Mallick, Piya Ghosh, Atanu Maiti, Israr Ahmed, Seemana Bhattacharya, Tapashi Mandal, Asit Manna, Koushik Roy, Sandeep Singh, Dipak Kumar Nayak, Paul T. Wilder, Joseph Markowitz, David Weber, Mrinal K. Ghosh, Samit Chattopadhyay, Rajdeep Guha, Aditya Konar, Santu Bandyopadhyay, Siddhartha Roy

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)344-358
Number of pages15
JournalBiopolymers - Peptide Science Section
Volume102
Issue number4
DOIs
StatePublished - Jul 1 2014

Bibliographical note

Publisher Copyright:
© 2014 Wiley Periodicals, Inc.

Keywords

  • Antitumor
  • Helix
  • Inhibitor
  • Peptides
  • Protein-protein interaction

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