title: A Constrained Helical Peptide Against S100A4 Inhibits Cell Motility in Tumor Cells.
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.
authors.affiliation: Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, 700 032, India.
authors.forename: Gitashri
authors.initials: G
authors.lastname: Naiya
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur PO, Bangalore, Karnataka, 560064, India.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kaypee
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur PO, Bangalore, Karnataka, 560064, India.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
authors.affiliation: Division of Structural Biology and Bioinformatics, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, 700 032, India.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Roy
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D024507:Nonmuscle Myosin Type IIA / Q000737:chemistry / Q000494:pharmacology; D024501:Nonmuscle Myosin Type IIB / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D024507:Nonmuscle Myosin Type IIA; D024501:Nonmuscle Myosin Type IIB
keywords: chemical biology; peptide; protein-protein interaction