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.

S100A4 in cancer progression and metastasis: A systematic review

“…IFN-γ-downregulation of S100A4 is also observed in OS, breast, and colon carcinoma cells, which was increased by the inhibition of S100A4 transcription, but not caused by the IFN-γ-mediated decrease in S100A4 mRNA stability [ 180 ]. A previous study has designed and developed a conformationally constrained helical peptide model of non-muscle myosin peptide to bind to S100A4 with a dissociation constant in the nanomolar range, for specifically inhibiting motility of cancer cells [ 181 ]. Similarly, other small molecule peptide-drug conjugates having high affinity to S100A4 could be also developed to control tumor metastasis [ 181 ].…”

“…A previous study has designed and developed a conformationally constrained helical peptide model of non-muscle myosin peptide to bind to S100A4 with a dissociation constant in the nanomolar range, for specifically inhibiting motility of cancer cells [ 181 ]. Similarly, other small molecule peptide-drug conjugates having high affinity to S100A4 could be also developed to control tumor metastasis [ 181 ].…”

Secreted S100A4 causes asthmatic airway epithelial barrier dysfunction induced by house dust mite extracts via activating VEGFA/VEGFR2 pathway

“…Intracellular S100A4 interacted with nonmuscle myosin heavy chain IIA in a calcium dependent process, resulting in the increase of cell motility and invasion 39,40 . And this protein also bound to Rhotekin and then formed a complex which mediated the invasion of cancer cells 41 . The direct interaction of S100A4 and tumor suppressor protein p53 was a prerequisite for cell apoptosis, proliferation and differentiation in cancer 42–44 .…”

“…39,40 And this protein also bound to Rhotekin and then formed a complex which mediated the invasion of cancer cells. 41 The direct interaction of S100A4 and tumor suppressor protein p53 was a prerequisite for cell apoptosis, proliferation and differentiation in cancer. [42][43][44] S100A4 was also involved in the formation of lipoprotein-α1/lipoprotein-β1 complex in vivo, and thereby regulated the cell adhesion and metastasis.…”

Constrained α-Helical Peptides as Inhibitors of Protein-Protein and Protein-DNA Interactions

“…Our group developed α-amino isobutyric acid (Aib) substituted conformationally-constrained helices as building blocks for constructing Protein-Protein interaction [27,104,105] and Protein-DNA interaction inhibitors. Tagged with the CPP (cell penetrating sequence) and the NLS (nuclear localization signal), the peptide constructs targeted against specific DNA sequence—henceforth, called synthetic transcription factors (STF)—accumulate in the nucleus and regulate the expressions of desired genes.…”