Cell migration modulating compounds

Ana Maria Schor (Inventor), Seth Lawrence Schor (Inventor), Rodolfo Marquez (Inventor), David George Norman (Inventor)

    Research output: Patent

    Abstract

    Migration Stimulating Factor (MSF) is a stress-response molecule expressed by epithelial and stromal cells in fetal skin and common human tumours. MSF is not normally present in healthy adult skin, but is transiently re-expressed during wound healing. Human recombinant MSF displays a number of potent bioactivities relevant to wound healing and cancer progression, including the stimulation of cell migration (target: carcinoma cells, keratinocytes, dermal fibroblasts, endothelial cells), stimulation of hyaluronan synthesis by fibroblasts, and angiogenesis in vivo and in vitro. MSF is a truncated isoform of fibronectin produced from the primary fibronectin gene transcript by a bypass of normal alternative splicing involving read-through of the intron separating exons III-1a and -1b. Intron retention results in the inclusion of a unique 30 bp coding sequence. MSF protein is consequently identical to the 70 kDa N-terminus of fibronectin, including nine type I and two type II modules, and terminates with the sequence coded by module III-1a and a unique decamer not present in any previously described "full-length" fibronectin isoform. The IGD (isoleucine, glycine, aspartate) tripeptide motif, a highly conserved feature of the fibronectin type I module, is present within the third, fifth, seventh and ninth constituent type I modules of MSF. Interestingly, synthetic trimer and tetramer peptides containing the IGD motif exhibit the same range of biological activities as those displayed by MSF. Furthermore, in vitro mutagenesis and analysis of IGDrecombinant constructs has demonstrated that the motogenic activity of MSF on target fibroblasts is mediated by the IGD sequences. Studies have implicated the related RGDamino acid motif (located in the tenth type III repeat module) in mediating the cell migrating stimulating effects of both native fibronectin and its cell-binding domain. Significantly, small RGD-containing synthetic peptides did not stimulate cell migration; indeed, these peptides inhibited the adhesive and migration stimulatory activity of larger protein domains contining the RGD motif by competition for receptor ligation. International patent application published under number WO 99/02674, relates to peptides containing the IGD motif and their use as cell migration modulators. There is a need to provide molecules which express MSF/IGD bioactivities and show improved stability compared to the IGD tripeptide. Such molecules may be useful as therapeutic agents for the management of patients with impaired wound healing and other pathologies requiring the stimulation of cell migration and angiogenesis. It is an object of the present invention to provide IGD mimetic molecules having MSF and/or IGD bioactivity, such as stimulatory and/or inhibitory activity.
    Original languageEnglish
    Patent numberEP1917012
    Publication statusPublished - 19 Oct 2011

    Fingerprint

    Fibronectins
    Cell Movement
    Wound Healing
    Peptides
    Fibroblasts
    Introns
    Skin
    Protein Isoforms
    Isoleucine
    Alternative Splicing
    Proxy
    Hyaluronic Acid
    Stromal Cells
    Keratinocytes
    Aspartic Acid
    Mutagenesis
    Adhesives
    Glycine
    Ligation
    Exons

    Cite this

    Schor, A. M., Schor, S. L., Marquez, R., & Norman, D. G. (2011). Cell migration modulating compounds. (Patent No. EP1917012).
    Schor, Ana Maria (Inventor) ; Schor, Seth Lawrence (Inventor) ; Marquez, Rodolfo (Inventor) ; Norman, David George (Inventor). / Cell migration modulating compounds. Patent No.: EP1917012.
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    title = "Cell migration modulating compounds",
    abstract = "Migration Stimulating Factor (MSF) is a stress-response molecule expressed by epithelial and stromal cells in fetal skin and common human tumours. MSF is not normally present in healthy adult skin, but is transiently re-expressed during wound healing. Human recombinant MSF displays a number of potent bioactivities relevant to wound healing and cancer progression, including the stimulation of cell migration (target: carcinoma cells, keratinocytes, dermal fibroblasts, endothelial cells), stimulation of hyaluronan synthesis by fibroblasts, and angiogenesis in vivo and in vitro. MSF is a truncated isoform of fibronectin produced from the primary fibronectin gene transcript by a bypass of normal alternative splicing involving read-through of the intron separating exons III-1a and -1b. Intron retention results in the inclusion of a unique 30 bp coding sequence. MSF protein is consequently identical to the 70 kDa N-terminus of fibronectin, including nine type I and two type II modules, and terminates with the sequence coded by module III-1a and a unique decamer not present in any previously described {"}full-length{"} fibronectin isoform. The IGD (isoleucine, glycine, aspartate) tripeptide motif, a highly conserved feature of the fibronectin type I module, is present within the third, fifth, seventh and ninth constituent type I modules of MSF. Interestingly, synthetic trimer and tetramer peptides containing the IGD motif exhibit the same range of biological activities as those displayed by MSF. Furthermore, in vitro mutagenesis and analysis of IGDrecombinant constructs has demonstrated that the motogenic activity of MSF on target fibroblasts is mediated by the IGD sequences. Studies have implicated the related RGDamino acid motif (located in the tenth type III repeat module) in mediating the cell migrating stimulating effects of both native fibronectin and its cell-binding domain. Significantly, small RGD-containing synthetic peptides did not stimulate cell migration; indeed, these peptides inhibited the adhesive and migration stimulatory activity of larger protein domains contining the RGD motif by competition for receptor ligation. International patent application published under number WO 99/02674, relates to peptides containing the IGD motif and their use as cell migration modulators. There is a need to provide molecules which express MSF/IGD bioactivities and show improved stability compared to the IGD tripeptide. Such molecules may be useful as therapeutic agents for the management of patients with impaired wound healing and other pathologies requiring the stimulation of cell migration and angiogenesis. It is an object of the present invention to provide IGD mimetic molecules having MSF and/or IGD bioactivity, such as stimulatory and/or inhibitory activity.",
    author = "Schor, {Ana Maria} and Schor, {Seth Lawrence} and Rodolfo Marquez and Norman, {David George}",
    year = "2011",
    month = "10",
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    type = "Patent",
    note = "EP1917012",

    }

    Schor, AM, Schor, SL, Marquez, R & Norman, DG 2011, Cell migration modulating compounds, Patent No. EP1917012.

    Cell migration modulating compounds. / Schor, Ana Maria (Inventor); Schor, Seth Lawrence (Inventor); Marquez, Rodolfo (Inventor); Norman, David George (Inventor).

    Patent No.: EP1917012.

    Research output: Patent

    TY - PAT

    T1 - Cell migration modulating compounds

    AU - Schor, Ana Maria

    AU - Schor, Seth Lawrence

    AU - Marquez, Rodolfo

    AU - Norman, David George

    PY - 2011/10/19

    Y1 - 2011/10/19

    N2 - Migration Stimulating Factor (MSF) is a stress-response molecule expressed by epithelial and stromal cells in fetal skin and common human tumours. MSF is not normally present in healthy adult skin, but is transiently re-expressed during wound healing. Human recombinant MSF displays a number of potent bioactivities relevant to wound healing and cancer progression, including the stimulation of cell migration (target: carcinoma cells, keratinocytes, dermal fibroblasts, endothelial cells), stimulation of hyaluronan synthesis by fibroblasts, and angiogenesis in vivo and in vitro. MSF is a truncated isoform of fibronectin produced from the primary fibronectin gene transcript by a bypass of normal alternative splicing involving read-through of the intron separating exons III-1a and -1b. Intron retention results in the inclusion of a unique 30 bp coding sequence. MSF protein is consequently identical to the 70 kDa N-terminus of fibronectin, including nine type I and two type II modules, and terminates with the sequence coded by module III-1a and a unique decamer not present in any previously described "full-length" fibronectin isoform. The IGD (isoleucine, glycine, aspartate) tripeptide motif, a highly conserved feature of the fibronectin type I module, is present within the third, fifth, seventh and ninth constituent type I modules of MSF. Interestingly, synthetic trimer and tetramer peptides containing the IGD motif exhibit the same range of biological activities as those displayed by MSF. Furthermore, in vitro mutagenesis and analysis of IGDrecombinant constructs has demonstrated that the motogenic activity of MSF on target fibroblasts is mediated by the IGD sequences. Studies have implicated the related RGDamino acid motif (located in the tenth type III repeat module) in mediating the cell migrating stimulating effects of both native fibronectin and its cell-binding domain. Significantly, small RGD-containing synthetic peptides did not stimulate cell migration; indeed, these peptides inhibited the adhesive and migration stimulatory activity of larger protein domains contining the RGD motif by competition for receptor ligation. International patent application published under number WO 99/02674, relates to peptides containing the IGD motif and their use as cell migration modulators. There is a need to provide molecules which express MSF/IGD bioactivities and show improved stability compared to the IGD tripeptide. Such molecules may be useful as therapeutic agents for the management of patients with impaired wound healing and other pathologies requiring the stimulation of cell migration and angiogenesis. It is an object of the present invention to provide IGD mimetic molecules having MSF and/or IGD bioactivity, such as stimulatory and/or inhibitory activity.

    AB - Migration Stimulating Factor (MSF) is a stress-response molecule expressed by epithelial and stromal cells in fetal skin and common human tumours. MSF is not normally present in healthy adult skin, but is transiently re-expressed during wound healing. Human recombinant MSF displays a number of potent bioactivities relevant to wound healing and cancer progression, including the stimulation of cell migration (target: carcinoma cells, keratinocytes, dermal fibroblasts, endothelial cells), stimulation of hyaluronan synthesis by fibroblasts, and angiogenesis in vivo and in vitro. MSF is a truncated isoform of fibronectin produced from the primary fibronectin gene transcript by a bypass of normal alternative splicing involving read-through of the intron separating exons III-1a and -1b. Intron retention results in the inclusion of a unique 30 bp coding sequence. MSF protein is consequently identical to the 70 kDa N-terminus of fibronectin, including nine type I and two type II modules, and terminates with the sequence coded by module III-1a and a unique decamer not present in any previously described "full-length" fibronectin isoform. The IGD (isoleucine, glycine, aspartate) tripeptide motif, a highly conserved feature of the fibronectin type I module, is present within the third, fifth, seventh and ninth constituent type I modules of MSF. Interestingly, synthetic trimer and tetramer peptides containing the IGD motif exhibit the same range of biological activities as those displayed by MSF. Furthermore, in vitro mutagenesis and analysis of IGDrecombinant constructs has demonstrated that the motogenic activity of MSF on target fibroblasts is mediated by the IGD sequences. Studies have implicated the related RGDamino acid motif (located in the tenth type III repeat module) in mediating the cell migrating stimulating effects of both native fibronectin and its cell-binding domain. Significantly, small RGD-containing synthetic peptides did not stimulate cell migration; indeed, these peptides inhibited the adhesive and migration stimulatory activity of larger protein domains contining the RGD motif by competition for receptor ligation. International patent application published under number WO 99/02674, relates to peptides containing the IGD motif and their use as cell migration modulators. There is a need to provide molecules which express MSF/IGD bioactivities and show improved stability compared to the IGD tripeptide. Such molecules may be useful as therapeutic agents for the management of patients with impaired wound healing and other pathologies requiring the stimulation of cell migration and angiogenesis. It is an object of the present invention to provide IGD mimetic molecules having MSF and/or IGD bioactivity, such as stimulatory and/or inhibitory activity.

    M3 - Patent

    M1 - EP1917012

    ER -

    Schor AM, Schor SL, Marquez R, Norman DG, inventors. Cell migration modulating compounds. EP1917012. 2011 Oct 19.