A Constrained Helical Peptide Against S100A4 Inhibits Cell Motility in Tumor Cells

Chemical Biology & Drug Design
Gitashri NaiyaSiddhartha Roy

Abstract

S100A4, a member of a calcium-regulated protein family, is involved in various cellular signaling pathways. From many studies over the last decade or so, it has become clear that it is involved in tumor metastasis, probably playing a determinative role. However, except the phenothiazine group of drugs, no significant inhibitor of S100A4 has been reported. Even the phenothiazines are very weak inhibitors of S100A4 action. In this study, we report design and development of a conformationally constrained helical peptide modeled on the non-muscle myosin peptide that binds to S100A4. This conformationally constrained peptide binds to S100A4 with a dissociation constant in the nanomolar range. We also synthesized a peptide for experimental control that bears several alanine mutations in the peptide-protein interface. We demonstrate that the former peptide specifically inhibits motility of H1299 and MCF-7 cells in a wound-healing assay. Structures of several S100A4-ligand complexes suggest that it may be possible to develop a smaller peptide-small molecule conjugate having high affinity for S100A4. Peptide-drug conjugates of this kind may play an important role in developing drug leads against this antimetastasis target.

References

Jul 10, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·Raja BanerjeeSiddhartha Roy
Sep 9, 2004·Science·Loren D WalenskyStanley J Korsmeyer
May 4, 2005·Cancer Research·Birgitte Grum-SchwensenNoona Ambartsumian
Nov 13, 2009·Nature·Raymond E MoelleringJames E Bradner
Dec 19, 2009·The American Journal of Pathology·Kjetil Boye, Gunhild M Maelandsmo
Apr 28, 2010·Proceedings of the National Academy of Sciences of the United States of America·Vladimir N MalashkevichAnne R Bresnick
Nov 16, 2010·Cancer Cell·Federico BernalLoren D Walensky
Apr 7, 2012·ACS Chemical Biology·Abhishek MazumderSiddhartha Roy
Dec 19, 2012·Cell Calcium·Danna B ZimmerMichael F Criscitiello

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Citations

Oct 27, 2017·Oncotarget·Fei FeiShiwu Zhang

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