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sar247799  (MedChemExpress)


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    MedChemExpress sar247799
    A-D. Activation of S1PR1, S1PR3, and S1PR5 by CYM5442, HY-X-1011, Ponesimod, or <t>SAR247799,</t> as measured via the BRET-based Gi dissociation assay. Data are presented as mean ± SEM; n = 3. All four compounds exhibit higher selectivity for S1PR1 compared to S1PR3 and S1PR5. No Gi signaling response is observed for S1PR2 and S1PR4 upon treatment with these agonists (data not shown). E-H. Free energy profiles along the activation pathways of S1PR1 (black), S1PR3 (blue), and S1PR5 (wheat) induced by CYM5442, HY-X-1011, Ponesimod, or SAR247799. The profiles are plotted as lines. TS: transition state; IS: intermediate state, structurally resembling the fully active conformation. The free energy differences between the IS/TS states and the inactive state are calculated and labeled using circles (TS) and squares (IS), respectively. I. Schematic illustration showing the activation of S1PR1, S1PR3, and S1PR5 by the four agonists—CYM5442, HY-X-1011, Ponesimod, and SAR247799. Solid arrows indicate strong activation, while dashed arrows represent weak activation. J. Cryo-EM density maps of S1PR1-Gi complexes bound with CYM5442, HY-X-1011, Ponesimod, or SAR247799. Ligands (yellow) are displayed within the density maps (gray mesh) on the right side of the models and are represented in stick form. K. Structural cartoon models of human S1PR1 in complex with Gi, scFv16, and each of the four agonists: CYM5442, HY-X-1011, Ponesimod, or SAR247799. In panels J–K, S1PR1 is colored marine, Gαi pale green, Gβ light blue, Gγ wheat, scFv16 gray, and agonists yellow.
    Sar247799, supplied by MedChemExpress, used in various techniques. Bioz Stars score: 94/100, based on 5 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
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    Images

    1) Product Images from "A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism"

    Article Title: A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism

    Journal: bioRxiv

    doi: 10.1101/2025.08.27.672536

    A-D. Activation of S1PR1, S1PR3, and S1PR5 by CYM5442, HY-X-1011, Ponesimod, or SAR247799, as measured via the BRET-based Gi dissociation assay. Data are presented as mean ± SEM; n = 3. All four compounds exhibit higher selectivity for S1PR1 compared to S1PR3 and S1PR5. No Gi signaling response is observed for S1PR2 and S1PR4 upon treatment with these agonists (data not shown). E-H. Free energy profiles along the activation pathways of S1PR1 (black), S1PR3 (blue), and S1PR5 (wheat) induced by CYM5442, HY-X-1011, Ponesimod, or SAR247799. The profiles are plotted as lines. TS: transition state; IS: intermediate state, structurally resembling the fully active conformation. The free energy differences between the IS/TS states and the inactive state are calculated and labeled using circles (TS) and squares (IS), respectively. I. Schematic illustration showing the activation of S1PR1, S1PR3, and S1PR5 by the four agonists—CYM5442, HY-X-1011, Ponesimod, and SAR247799. Solid arrows indicate strong activation, while dashed arrows represent weak activation. J. Cryo-EM density maps of S1PR1-Gi complexes bound with CYM5442, HY-X-1011, Ponesimod, or SAR247799. Ligands (yellow) are displayed within the density maps (gray mesh) on the right side of the models and are represented in stick form. K. Structural cartoon models of human S1PR1 in complex with Gi, scFv16, and each of the four agonists: CYM5442, HY-X-1011, Ponesimod, or SAR247799. In panels J–K, S1PR1 is colored marine, Gαi pale green, Gβ light blue, Gγ wheat, scFv16 gray, and agonists yellow.
    Figure Legend Snippet: A-D. Activation of S1PR1, S1PR3, and S1PR5 by CYM5442, HY-X-1011, Ponesimod, or SAR247799, as measured via the BRET-based Gi dissociation assay. Data are presented as mean ± SEM; n = 3. All four compounds exhibit higher selectivity for S1PR1 compared to S1PR3 and S1PR5. No Gi signaling response is observed for S1PR2 and S1PR4 upon treatment with these agonists (data not shown). E-H. Free energy profiles along the activation pathways of S1PR1 (black), S1PR3 (blue), and S1PR5 (wheat) induced by CYM5442, HY-X-1011, Ponesimod, or SAR247799. The profiles are plotted as lines. TS: transition state; IS: intermediate state, structurally resembling the fully active conformation. The free energy differences between the IS/TS states and the inactive state are calculated and labeled using circles (TS) and squares (IS), respectively. I. Schematic illustration showing the activation of S1PR1, S1PR3, and S1PR5 by the four agonists—CYM5442, HY-X-1011, Ponesimod, and SAR247799. Solid arrows indicate strong activation, while dashed arrows represent weak activation. J. Cryo-EM density maps of S1PR1-Gi complexes bound with CYM5442, HY-X-1011, Ponesimod, or SAR247799. Ligands (yellow) are displayed within the density maps (gray mesh) on the right side of the models and are represented in stick form. K. Structural cartoon models of human S1PR1 in complex with Gi, scFv16, and each of the four agonists: CYM5442, HY-X-1011, Ponesimod, or SAR247799. In panels J–K, S1PR1 is colored marine, Gαi pale green, Gβ light blue, Gγ wheat, scFv16 gray, and agonists yellow.

    Techniques Used: Activation Assay, Labeling, Cryo-EM Sample Prep

    A-D. Residues within the ligand-binding pocket that interact with CYM5442 (A) , HY-X-1011 (B) , Ponesimod (C ), or SAR247799 (D) . Hydrogen bonds are indicated by green lines, with distances labeled accordingly. E. Key binding pocket residues critical for S1PR1 activation mediated by CYM5442, HY-X-1011, Ponesimod, or SAR247799, as confirmed by the BRET-based Gi dissociation assay. In this assay, most binding residues were evaluated through alanine substitution. The effects of residue mutations on the Gi signaling response are represented as follows: white circles with gray borders > dark gray circles > light gray circles. White circles with gray borders indicate that alanine substitution at that position almost completely abolished S1PR1 activation. Corresponding data are provided in Table S2 of the Supporting Information.
    Figure Legend Snippet: A-D. Residues within the ligand-binding pocket that interact with CYM5442 (A) , HY-X-1011 (B) , Ponesimod (C ), or SAR247799 (D) . Hydrogen bonds are indicated by green lines, with distances labeled accordingly. E. Key binding pocket residues critical for S1PR1 activation mediated by CYM5442, HY-X-1011, Ponesimod, or SAR247799, as confirmed by the BRET-based Gi dissociation assay. In this assay, most binding residues were evaluated through alanine substitution. The effects of residue mutations on the Gi signaling response are represented as follows: white circles with gray borders > dark gray circles > light gray circles. White circles with gray borders indicate that alanine substitution at that position almost completely abolished S1PR1 activation. Corresponding data are provided in Table S2 of the Supporting Information.

    Techniques Used: Ligand Binding Assay, Labeling, Binding Assay, Activation Assay, Residue

    A-D. Nonconserved residues in the ligand binding pocket of S1PR1 and S1PR3. CYM5442-, HY-X-1011-, Ponesimod-, or SAR247799-bound S1PR1 are superimposed with S1PR3 (PDB: 7EW3) in panels A-D, respectively. Residues of S1PR1 (marine) and S1PR3 (gray) are shown as sticks. Molecules are shown as sticks and colored yellow (CYM5442), pink (HY-X-1011), light blue (Ponesimod), and cyan (SAR247799). E-L. BRET-based Gi dissociation assays showing activation of swapped mutants of S1PR1 and S1PR3 by the four agonists. Data are presented as mean ± SEM; n=3.
    Figure Legend Snippet: A-D. Nonconserved residues in the ligand binding pocket of S1PR1 and S1PR3. CYM5442-, HY-X-1011-, Ponesimod-, or SAR247799-bound S1PR1 are superimposed with S1PR3 (PDB: 7EW3) in panels A-D, respectively. Residues of S1PR1 (marine) and S1PR3 (gray) are shown as sticks. Molecules are shown as sticks and colored yellow (CYM5442), pink (HY-X-1011), light blue (Ponesimod), and cyan (SAR247799). E-L. BRET-based Gi dissociation assays showing activation of swapped mutants of S1PR1 and S1PR3 by the four agonists. Data are presented as mean ± SEM; n=3.

    Techniques Used: Ligand Binding Assay, Activation Assay

    A-D. Nonconserved residues in the ligand binding pocket of S1PR1 and S1PR5. CYM5442-, HY-X-1011-, Ponesimod-, or SAR247799-bound S1PR1 are superimposed with S1PR5(PDB: 7EW1). Residues of S1PR1 (marine) and S1PR5 (orange) are shown as sticks. Molecules are shown as sticks and colored yellow (CYM5442), pink (HY-X-1011), light blue (Ponesimod), and cyan (SAR247799). Orange dashed lines indicate the distances between the agonist and specific residues. Three nonconserved residues located at the bottom of S1PR1, S1PR3, and S1PR5 are enclosed within dashed-line rounded rectangles (orange). E–L. BRET-based Gi dissociation assays showing activation of S1PR1 and S1PR5 swapped mutants by the four agonists. Data are presented as mean ± SEM; n=3.
    Figure Legend Snippet: A-D. Nonconserved residues in the ligand binding pocket of S1PR1 and S1PR5. CYM5442-, HY-X-1011-, Ponesimod-, or SAR247799-bound S1PR1 are superimposed with S1PR5(PDB: 7EW1). Residues of S1PR1 (marine) and S1PR5 (orange) are shown as sticks. Molecules are shown as sticks and colored yellow (CYM5442), pink (HY-X-1011), light blue (Ponesimod), and cyan (SAR247799). Orange dashed lines indicate the distances between the agonist and specific residues. Three nonconserved residues located at the bottom of S1PR1, S1PR3, and S1PR5 are enclosed within dashed-line rounded rectangles (orange). E–L. BRET-based Gi dissociation assays showing activation of S1PR1 and S1PR5 swapped mutants by the four agonists. Data are presented as mean ± SEM; n=3.

    Techniques Used: Ligand Binding Assay, Activation Assay

    A–C. Three nonconserved residues are located at the bottom of the ligand-binding pockets in S1PR1, S1PR3, and S1PR5. Electrostatic potentials of the pocket and protein surface are displayed: red indicates negative charge, blue indicates positive charge, and white represents hydrophobic regions. The pocket-cutting surface is shown in gray, with all surfaces rendered as semitransparent. Structures include S1PR1 bound to CYM5442 ( A ), S1PR3 bound to S1P (PDB ID: 7EW3) ( B ), and S1PR5 bound to Siponimod ( C ). The bottom portions of these pockets are open toward the intracellular side. Ligands and the three nonconserved residues at the base of each pocket are shown in stick representation. D. Superposition of active S1PR1 structures bound to CYM5442, HY-X-1011, Ponesimod, or SAR247799 with the inactive form of S1PR1 (PDB ID: 3V2Y). Residues are shown as sticks, and red lines indicate structural differences between active and inactive conformations. E. Structural comparison of the five S1PR1 agonist molecules. Binding modes of the five agonists within the S1PR1 pocket are presented. S1P (gray) corresponds to the structure bound with S1PR3 (PDB ID: 7EW3), while S1P (red) refers to the complex with S1PR1 (PDB ID: 7VIE). The gray background highlights conserved features among four of the molecules. F–H. Distances between the tails of CYM5442, HY-X-1011, Ponesimod, or SAR247799 and the Cα atom of residue 5.50 in S1PR1, S1PR3, and S1PR5 during receptor activation—from the inactive to active state—calculated using the TAPS method in molecular dynamics simulations.
    Figure Legend Snippet: A–C. Three nonconserved residues are located at the bottom of the ligand-binding pockets in S1PR1, S1PR3, and S1PR5. Electrostatic potentials of the pocket and protein surface are displayed: red indicates negative charge, blue indicates positive charge, and white represents hydrophobic regions. The pocket-cutting surface is shown in gray, with all surfaces rendered as semitransparent. Structures include S1PR1 bound to CYM5442 ( A ), S1PR3 bound to S1P (PDB ID: 7EW3) ( B ), and S1PR5 bound to Siponimod ( C ). The bottom portions of these pockets are open toward the intracellular side. Ligands and the three nonconserved residues at the base of each pocket are shown in stick representation. D. Superposition of active S1PR1 structures bound to CYM5442, HY-X-1011, Ponesimod, or SAR247799 with the inactive form of S1PR1 (PDB ID: 3V2Y). Residues are shown as sticks, and red lines indicate structural differences between active and inactive conformations. E. Structural comparison of the five S1PR1 agonist molecules. Binding modes of the five agonists within the S1PR1 pocket are presented. S1P (gray) corresponds to the structure bound with S1PR3 (PDB ID: 7EW3), while S1P (red) refers to the complex with S1PR1 (PDB ID: 7VIE). The gray background highlights conserved features among four of the molecules. F–H. Distances between the tails of CYM5442, HY-X-1011, Ponesimod, or SAR247799 and the Cα atom of residue 5.50 in S1PR1, S1PR3, and S1PR5 during receptor activation—from the inactive to active state—calculated using the TAPS method in molecular dynamics simulations.

    Techniques Used: Ligand Binding Assay, Comparison, Binding Assay, Residue, Activation Assay

    A-H. Superimposition of CYM5442, HY-X-1011, Ponesimod, or SAR247799 bound to S1PR1 with S1P bound to S1PR1 (PDB: 7VIE) and S1PR3 (PDB: 7EW3). Residues of S1PR1 (marine) and S1PR3 (gray) are shown as sticks. Molecules are displayed as sticks colored as follows: yellow for CYM5442, pink for HY-X-1011, light blue for Ponesimod, cyan for SAR247799, red for S1P (from 7VIE), and gray for Siponimod (from 7EW3). I-L. Superimposition of CYM5442, HY-X-1011, Ponesimod, SAR247799, and S1P in S1PR1 (PDB: 7VIE) with Siponimod in S1PR5 (PDB: 7EW1). Four residues of S1PR1 (marine) and S1PR5 (yellow-orange) are shown as sticks. Ligands are represented as sticks and colored as follows: yellow for CYM5442, pink for HY-X-1011, light blue for Ponesimod, cyan for SAR247799, red for S1P (from 7VIE), and yellow-orange for Siponimod (from 7EW1). Dashed gray circles highlight differences in binding poses between Siponimod and CYM5442, HY-X-1011, or Ponesimod.
    Figure Legend Snippet: A-H. Superimposition of CYM5442, HY-X-1011, Ponesimod, or SAR247799 bound to S1PR1 with S1P bound to S1PR1 (PDB: 7VIE) and S1PR3 (PDB: 7EW3). Residues of S1PR1 (marine) and S1PR3 (gray) are shown as sticks. Molecules are displayed as sticks colored as follows: yellow for CYM5442, pink for HY-X-1011, light blue for Ponesimod, cyan for SAR247799, red for S1P (from 7VIE), and gray for Siponimod (from 7EW3). I-L. Superimposition of CYM5442, HY-X-1011, Ponesimod, SAR247799, and S1P in S1PR1 (PDB: 7VIE) with Siponimod in S1PR5 (PDB: 7EW1). Four residues of S1PR1 (marine) and S1PR5 (yellow-orange) are shown as sticks. Ligands are represented as sticks and colored as follows: yellow for CYM5442, pink for HY-X-1011, light blue for Ponesimod, cyan for SAR247799, red for S1P (from 7VIE), and yellow-orange for Siponimod (from 7EW1). Dashed gray circles highlight differences in binding poses between Siponimod and CYM5442, HY-X-1011, or Ponesimod.

    Techniques Used: Binding Assay


    Figure Legend Snippet:

    Techniques Used:


    Figure Legend Snippet:

    Techniques Used:



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    A-D. Activation of S1PR1, S1PR3, and S1PR5 by CYM5442, HY-X-1011, Ponesimod, or <t>SAR247799,</t> as measured via the BRET-based Gi dissociation assay. Data are presented as mean ± SEM; n = 3. All four compounds exhibit higher selectivity for S1PR1 compared to S1PR3 and S1PR5. No Gi signaling response is observed for S1PR2 and S1PR4 upon treatment with these agonists (data not shown). E-H. Free energy profiles along the activation pathways of S1PR1 (black), S1PR3 (blue), and S1PR5 (wheat) induced by CYM5442, HY-X-1011, Ponesimod, or SAR247799. The profiles are plotted as lines. TS: transition state; IS: intermediate state, structurally resembling the fully active conformation. The free energy differences between the IS/TS states and the inactive state are calculated and labeled using circles (TS) and squares (IS), respectively. I. Schematic illustration showing the activation of S1PR1, S1PR3, and S1PR5 by the four agonists—CYM5442, HY-X-1011, Ponesimod, and SAR247799. Solid arrows indicate strong activation, while dashed arrows represent weak activation. J. Cryo-EM density maps of S1PR1-Gi complexes bound with CYM5442, HY-X-1011, Ponesimod, or SAR247799. Ligands (yellow) are displayed within the density maps (gray mesh) on the right side of the models and are represented in stick form. K. Structural cartoon models of human S1PR1 in complex with Gi, scFv16, and each of the four agonists: CYM5442, HY-X-1011, Ponesimod, or SAR247799. In panels J–K, S1PR1 is colored marine, Gαi pale green, Gβ light blue, Gγ wheat, scFv16 gray, and agonists yellow.
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    A-D. Activation of S1PR1, S1PR3, and S1PR5 by CYM5442, HY-X-1011, Ponesimod, or SAR247799, as measured via the BRET-based Gi dissociation assay. Data are presented as mean ± SEM; n = 3. All four compounds exhibit higher selectivity for S1PR1 compared to S1PR3 and S1PR5. No Gi signaling response is observed for S1PR2 and S1PR4 upon treatment with these agonists (data not shown). E-H. Free energy profiles along the activation pathways of S1PR1 (black), S1PR3 (blue), and S1PR5 (wheat) induced by CYM5442, HY-X-1011, Ponesimod, or SAR247799. The profiles are plotted as lines. TS: transition state; IS: intermediate state, structurally resembling the fully active conformation. The free energy differences between the IS/TS states and the inactive state are calculated and labeled using circles (TS) and squares (IS), respectively. I. Schematic illustration showing the activation of S1PR1, S1PR3, and S1PR5 by the four agonists—CYM5442, HY-X-1011, Ponesimod, and SAR247799. Solid arrows indicate strong activation, while dashed arrows represent weak activation. J. Cryo-EM density maps of S1PR1-Gi complexes bound with CYM5442, HY-X-1011, Ponesimod, or SAR247799. Ligands (yellow) are displayed within the density maps (gray mesh) on the right side of the models and are represented in stick form. K. Structural cartoon models of human S1PR1 in complex with Gi, scFv16, and each of the four agonists: CYM5442, HY-X-1011, Ponesimod, or SAR247799. In panels J–K, S1PR1 is colored marine, Gαi pale green, Gβ light blue, Gγ wheat, scFv16 gray, and agonists yellow.

    Journal: bioRxiv

    Article Title: A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism

    doi: 10.1101/2025.08.27.672536

    Figure Lengend Snippet: A-D. Activation of S1PR1, S1PR3, and S1PR5 by CYM5442, HY-X-1011, Ponesimod, or SAR247799, as measured via the BRET-based Gi dissociation assay. Data are presented as mean ± SEM; n = 3. All four compounds exhibit higher selectivity for S1PR1 compared to S1PR3 and S1PR5. No Gi signaling response is observed for S1PR2 and S1PR4 upon treatment with these agonists (data not shown). E-H. Free energy profiles along the activation pathways of S1PR1 (black), S1PR3 (blue), and S1PR5 (wheat) induced by CYM5442, HY-X-1011, Ponesimod, or SAR247799. The profiles are plotted as lines. TS: transition state; IS: intermediate state, structurally resembling the fully active conformation. The free energy differences between the IS/TS states and the inactive state are calculated and labeled using circles (TS) and squares (IS), respectively. I. Schematic illustration showing the activation of S1PR1, S1PR3, and S1PR5 by the four agonists—CYM5442, HY-X-1011, Ponesimod, and SAR247799. Solid arrows indicate strong activation, while dashed arrows represent weak activation. J. Cryo-EM density maps of S1PR1-Gi complexes bound with CYM5442, HY-X-1011, Ponesimod, or SAR247799. Ligands (yellow) are displayed within the density maps (gray mesh) on the right side of the models and are represented in stick form. K. Structural cartoon models of human S1PR1 in complex with Gi, scFv16, and each of the four agonists: CYM5442, HY-X-1011, Ponesimod, or SAR247799. In panels J–K, S1PR1 is colored marine, Gαi pale green, Gβ light blue, Gγ wheat, scFv16 gray, and agonists yellow.

    Article Snippet: Ponesimod, CYM5442, and SAR247799 were purchased from MedChemExpress (MCE).

    Techniques: Activation Assay, Labeling, Cryo-EM Sample Prep

    A-D. Residues within the ligand-binding pocket that interact with CYM5442 (A) , HY-X-1011 (B) , Ponesimod (C ), or SAR247799 (D) . Hydrogen bonds are indicated by green lines, with distances labeled accordingly. E. Key binding pocket residues critical for S1PR1 activation mediated by CYM5442, HY-X-1011, Ponesimod, or SAR247799, as confirmed by the BRET-based Gi dissociation assay. In this assay, most binding residues were evaluated through alanine substitution. The effects of residue mutations on the Gi signaling response are represented as follows: white circles with gray borders > dark gray circles > light gray circles. White circles with gray borders indicate that alanine substitution at that position almost completely abolished S1PR1 activation. Corresponding data are provided in Table S2 of the Supporting Information.

    Journal: bioRxiv

    Article Title: A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism

    doi: 10.1101/2025.08.27.672536

    Figure Lengend Snippet: A-D. Residues within the ligand-binding pocket that interact with CYM5442 (A) , HY-X-1011 (B) , Ponesimod (C ), or SAR247799 (D) . Hydrogen bonds are indicated by green lines, with distances labeled accordingly. E. Key binding pocket residues critical for S1PR1 activation mediated by CYM5442, HY-X-1011, Ponesimod, or SAR247799, as confirmed by the BRET-based Gi dissociation assay. In this assay, most binding residues were evaluated through alanine substitution. The effects of residue mutations on the Gi signaling response are represented as follows: white circles with gray borders > dark gray circles > light gray circles. White circles with gray borders indicate that alanine substitution at that position almost completely abolished S1PR1 activation. Corresponding data are provided in Table S2 of the Supporting Information.

    Article Snippet: Ponesimod, CYM5442, and SAR247799 were purchased from MedChemExpress (MCE).

    Techniques: Ligand Binding Assay, Labeling, Binding Assay, Activation Assay, Residue

    A-D. Nonconserved residues in the ligand binding pocket of S1PR1 and S1PR3. CYM5442-, HY-X-1011-, Ponesimod-, or SAR247799-bound S1PR1 are superimposed with S1PR3 (PDB: 7EW3) in panels A-D, respectively. Residues of S1PR1 (marine) and S1PR3 (gray) are shown as sticks. Molecules are shown as sticks and colored yellow (CYM5442), pink (HY-X-1011), light blue (Ponesimod), and cyan (SAR247799). E-L. BRET-based Gi dissociation assays showing activation of swapped mutants of S1PR1 and S1PR3 by the four agonists. Data are presented as mean ± SEM; n=3.

    Journal: bioRxiv

    Article Title: A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism

    doi: 10.1101/2025.08.27.672536

    Figure Lengend Snippet: A-D. Nonconserved residues in the ligand binding pocket of S1PR1 and S1PR3. CYM5442-, HY-X-1011-, Ponesimod-, or SAR247799-bound S1PR1 are superimposed with S1PR3 (PDB: 7EW3) in panels A-D, respectively. Residues of S1PR1 (marine) and S1PR3 (gray) are shown as sticks. Molecules are shown as sticks and colored yellow (CYM5442), pink (HY-X-1011), light blue (Ponesimod), and cyan (SAR247799). E-L. BRET-based Gi dissociation assays showing activation of swapped mutants of S1PR1 and S1PR3 by the four agonists. Data are presented as mean ± SEM; n=3.

    Article Snippet: Ponesimod, CYM5442, and SAR247799 were purchased from MedChemExpress (MCE).

    Techniques: Ligand Binding Assay, Activation Assay

    A-D. Nonconserved residues in the ligand binding pocket of S1PR1 and S1PR5. CYM5442-, HY-X-1011-, Ponesimod-, or SAR247799-bound S1PR1 are superimposed with S1PR5(PDB: 7EW1). Residues of S1PR1 (marine) and S1PR5 (orange) are shown as sticks. Molecules are shown as sticks and colored yellow (CYM5442), pink (HY-X-1011), light blue (Ponesimod), and cyan (SAR247799). Orange dashed lines indicate the distances between the agonist and specific residues. Three nonconserved residues located at the bottom of S1PR1, S1PR3, and S1PR5 are enclosed within dashed-line rounded rectangles (orange). E–L. BRET-based Gi dissociation assays showing activation of S1PR1 and S1PR5 swapped mutants by the four agonists. Data are presented as mean ± SEM; n=3.

    Journal: bioRxiv

    Article Title: A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism

    doi: 10.1101/2025.08.27.672536

    Figure Lengend Snippet: A-D. Nonconserved residues in the ligand binding pocket of S1PR1 and S1PR5. CYM5442-, HY-X-1011-, Ponesimod-, or SAR247799-bound S1PR1 are superimposed with S1PR5(PDB: 7EW1). Residues of S1PR1 (marine) and S1PR5 (orange) are shown as sticks. Molecules are shown as sticks and colored yellow (CYM5442), pink (HY-X-1011), light blue (Ponesimod), and cyan (SAR247799). Orange dashed lines indicate the distances between the agonist and specific residues. Three nonconserved residues located at the bottom of S1PR1, S1PR3, and S1PR5 are enclosed within dashed-line rounded rectangles (orange). E–L. BRET-based Gi dissociation assays showing activation of S1PR1 and S1PR5 swapped mutants by the four agonists. Data are presented as mean ± SEM; n=3.

    Article Snippet: Ponesimod, CYM5442, and SAR247799 were purchased from MedChemExpress (MCE).

    Techniques: Ligand Binding Assay, Activation Assay

    A–C. Three nonconserved residues are located at the bottom of the ligand-binding pockets in S1PR1, S1PR3, and S1PR5. Electrostatic potentials of the pocket and protein surface are displayed: red indicates negative charge, blue indicates positive charge, and white represents hydrophobic regions. The pocket-cutting surface is shown in gray, with all surfaces rendered as semitransparent. Structures include S1PR1 bound to CYM5442 ( A ), S1PR3 bound to S1P (PDB ID: 7EW3) ( B ), and S1PR5 bound to Siponimod ( C ). The bottom portions of these pockets are open toward the intracellular side. Ligands and the three nonconserved residues at the base of each pocket are shown in stick representation. D. Superposition of active S1PR1 structures bound to CYM5442, HY-X-1011, Ponesimod, or SAR247799 with the inactive form of S1PR1 (PDB ID: 3V2Y). Residues are shown as sticks, and red lines indicate structural differences between active and inactive conformations. E. Structural comparison of the five S1PR1 agonist molecules. Binding modes of the five agonists within the S1PR1 pocket are presented. S1P (gray) corresponds to the structure bound with S1PR3 (PDB ID: 7EW3), while S1P (red) refers to the complex with S1PR1 (PDB ID: 7VIE). The gray background highlights conserved features among four of the molecules. F–H. Distances between the tails of CYM5442, HY-X-1011, Ponesimod, or SAR247799 and the Cα atom of residue 5.50 in S1PR1, S1PR3, and S1PR5 during receptor activation—from the inactive to active state—calculated using the TAPS method in molecular dynamics simulations.

    Journal: bioRxiv

    Article Title: A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism

    doi: 10.1101/2025.08.27.672536

    Figure Lengend Snippet: A–C. Three nonconserved residues are located at the bottom of the ligand-binding pockets in S1PR1, S1PR3, and S1PR5. Electrostatic potentials of the pocket and protein surface are displayed: red indicates negative charge, blue indicates positive charge, and white represents hydrophobic regions. The pocket-cutting surface is shown in gray, with all surfaces rendered as semitransparent. Structures include S1PR1 bound to CYM5442 ( A ), S1PR3 bound to S1P (PDB ID: 7EW3) ( B ), and S1PR5 bound to Siponimod ( C ). The bottom portions of these pockets are open toward the intracellular side. Ligands and the three nonconserved residues at the base of each pocket are shown in stick representation. D. Superposition of active S1PR1 structures bound to CYM5442, HY-X-1011, Ponesimod, or SAR247799 with the inactive form of S1PR1 (PDB ID: 3V2Y). Residues are shown as sticks, and red lines indicate structural differences between active and inactive conformations. E. Structural comparison of the five S1PR1 agonist molecules. Binding modes of the five agonists within the S1PR1 pocket are presented. S1P (gray) corresponds to the structure bound with S1PR3 (PDB ID: 7EW3), while S1P (red) refers to the complex with S1PR1 (PDB ID: 7VIE). The gray background highlights conserved features among four of the molecules. F–H. Distances between the tails of CYM5442, HY-X-1011, Ponesimod, or SAR247799 and the Cα atom of residue 5.50 in S1PR1, S1PR3, and S1PR5 during receptor activation—from the inactive to active state—calculated using the TAPS method in molecular dynamics simulations.

    Article Snippet: Ponesimod, CYM5442, and SAR247799 were purchased from MedChemExpress (MCE).

    Techniques: Ligand Binding Assay, Comparison, Binding Assay, Residue, Activation Assay

    A-H. Superimposition of CYM5442, HY-X-1011, Ponesimod, or SAR247799 bound to S1PR1 with S1P bound to S1PR1 (PDB: 7VIE) and S1PR3 (PDB: 7EW3). Residues of S1PR1 (marine) and S1PR3 (gray) are shown as sticks. Molecules are displayed as sticks colored as follows: yellow for CYM5442, pink for HY-X-1011, light blue for Ponesimod, cyan for SAR247799, red for S1P (from 7VIE), and gray for Siponimod (from 7EW3). I-L. Superimposition of CYM5442, HY-X-1011, Ponesimod, SAR247799, and S1P in S1PR1 (PDB: 7VIE) with Siponimod in S1PR5 (PDB: 7EW1). Four residues of S1PR1 (marine) and S1PR5 (yellow-orange) are shown as sticks. Ligands are represented as sticks and colored as follows: yellow for CYM5442, pink for HY-X-1011, light blue for Ponesimod, cyan for SAR247799, red for S1P (from 7VIE), and yellow-orange for Siponimod (from 7EW1). Dashed gray circles highlight differences in binding poses between Siponimod and CYM5442, HY-X-1011, or Ponesimod.

    Journal: bioRxiv

    Article Title: A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism

    doi: 10.1101/2025.08.27.672536

    Figure Lengend Snippet: A-H. Superimposition of CYM5442, HY-X-1011, Ponesimod, or SAR247799 bound to S1PR1 with S1P bound to S1PR1 (PDB: 7VIE) and S1PR3 (PDB: 7EW3). Residues of S1PR1 (marine) and S1PR3 (gray) are shown as sticks. Molecules are displayed as sticks colored as follows: yellow for CYM5442, pink for HY-X-1011, light blue for Ponesimod, cyan for SAR247799, red for S1P (from 7VIE), and gray for Siponimod (from 7EW3). I-L. Superimposition of CYM5442, HY-X-1011, Ponesimod, SAR247799, and S1P in S1PR1 (PDB: 7VIE) with Siponimod in S1PR5 (PDB: 7EW1). Four residues of S1PR1 (marine) and S1PR5 (yellow-orange) are shown as sticks. Ligands are represented as sticks and colored as follows: yellow for CYM5442, pink for HY-X-1011, light blue for Ponesimod, cyan for SAR247799, red for S1P (from 7VIE), and yellow-orange for Siponimod (from 7EW1). Dashed gray circles highlight differences in binding poses between Siponimod and CYM5442, HY-X-1011, or Ponesimod.

    Article Snippet: Ponesimod, CYM5442, and SAR247799 were purchased from MedChemExpress (MCE).

    Techniques: Binding Assay

    Journal: bioRxiv

    Article Title: A Multi-Disciplinary Framework for Decoding S1PR1-Selective Agonism

    doi: 10.1101/2025.08.27.672536

    Figure Lengend Snippet:

    Article Snippet: Ponesimod, CYM5442, and SAR247799 were purchased from MedChemExpress (MCE).

    Techniques:

    Ob-ZSF1 rats were randomized on E/e’ parameter from doppler echocardiographic analysis. For adult animal study, Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 11 and Ob-ZSF1-SAR247799 N = 11. For aged animals study Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 7 and Ob-ZSF1-SAR247799 N = 7; N = number of rats.

    Journal: PLoS ONE

    Article Title: A G-protein-biased S1P 1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

    doi: 10.1371/journal.pone.0257929

    Figure Lengend Snippet: Ob-ZSF1 rats were randomized on E/e’ parameter from doppler echocardiographic analysis. For adult animal study, Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 11 and Ob-ZSF1-SAR247799 N = 11. For aged animals study Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 7 and Ob-ZSF1-SAR247799 N = 7; N = number of rats.

    Article Snippet: Ob-ZSF1 rats were randomized based on the E/e’ value to a control chow diet (Ob-ZSF1-CTRL N = 7) or to a diet with chow supplemented with 0.025% (w/w) SAR247799 (Ob-ZSF1-SAR247799 N = 7), (SSNIFF Spezialdiäten GmbH).

    Techniques:

    Diastolic function was evaluated by (A) E/e’ ratio (B) septal peak e’ wave velocity at mitral annulus level and (C) mitral valve peak E wave velocity. Cardiac systolic function was assessed by (D) ejection fraction, (E) end-diastolic volume, (F) end-systolic volume, (G) stroke volume and (H) cardiac index. Data are expressed mean ± SEM, except E, e’, E/e’, end-systolic volume, stroke volume and which are expressed as median ± IQR. † p<0.05, ††† p<0.001: comparison of Le-ZSF1-CTRL to Ob-ZSF1-CTRL using a Student t-test except for E/e’ and stroke volume for adult animals and for E wave for aged animals for which a Wilcoxon test was performed. ‡ p<0.05, ‡‡ p<0.01: p-values obtained from the comparison between Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 using a Student t-test except for E/e’ for adult animals and for E wave for aged animals for which a Wilcoxon test was performed. For adult animals, Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 11 and Ob-ZSF1-SAR247799 N = 11. For aged animals Le-ZSF1-CTRL N = 8–9, Ob-ZSF1-CTRL N = 6–7 and Ob-ZSF1-SAR247799 N = 7; N = number of rats. A lower number of n values is due to technical issue in echocardiography data acquisition.

    Journal: PLoS ONE

    Article Title: A G-protein-biased S1P 1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

    doi: 10.1371/journal.pone.0257929

    Figure Lengend Snippet: Diastolic function was evaluated by (A) E/e’ ratio (B) septal peak e’ wave velocity at mitral annulus level and (C) mitral valve peak E wave velocity. Cardiac systolic function was assessed by (D) ejection fraction, (E) end-diastolic volume, (F) end-systolic volume, (G) stroke volume and (H) cardiac index. Data are expressed mean ± SEM, except E, e’, E/e’, end-systolic volume, stroke volume and which are expressed as median ± IQR. † p<0.05, ††† p<0.001: comparison of Le-ZSF1-CTRL to Ob-ZSF1-CTRL using a Student t-test except for E/e’ and stroke volume for adult animals and for E wave for aged animals for which a Wilcoxon test was performed. ‡ p<0.05, ‡‡ p<0.01: p-values obtained from the comparison between Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 using a Student t-test except for E/e’ for adult animals and for E wave for aged animals for which a Wilcoxon test was performed. For adult animals, Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 11 and Ob-ZSF1-SAR247799 N = 11. For aged animals Le-ZSF1-CTRL N = 8–9, Ob-ZSF1-CTRL N = 6–7 and Ob-ZSF1-SAR247799 N = 7; N = number of rats. A lower number of n values is due to technical issue in echocardiography data acquisition.

    Article Snippet: Ob-ZSF1 rats were randomized based on the E/e’ value to a control chow diet (Ob-ZSF1-CTRL N = 7) or to a diet with chow supplemented with 0.025% (w/w) SAR247799 (Ob-ZSF1-SAR247799 N = 7), (SSNIFF Spezialdiäten GmbH).

    Techniques:

    (A) Heart weight/tibia length, (B) left atrial weight/tibia length, (C) right atrial weight/tibia length, (D) interventricular septum thickness at end-diastole (IVSd), (E) interventricular septum thickness at end-systole (IVSs), (F) left ventricular posterior wall thickness at end-diastole (LVPWd), (G) left ventricular posterior wall thickness at end-systole (LVPWs). Data expressed as mean ± SEM, except IVSd and LVPWd which are expressed as median ± IQR. †† p<0.01, ††† p<0.001: comparison of Le-ZSF1-CTRL to Ob-ZSF1-CTRL using a Student t-test, except LVPWd (adult animals) for which a Wilcoxon test was performed. ‡ p<0.05, ‡‡ p<0.01, ‡‡‡ p<0.001: comparison between Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 using a Student t-test, except LVPWd (adult animals) for which a Wilcoxon test was performed. For adult animals, Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 11 and Ob-ZSF1-SAR247799 N = 10–11. For aged animals Le-ZSF1-CTRL N = 8–9, Ob-ZSF1-CTRL N = 6–7 and Ob-ZSF1-SAR247799 N = 7; N = number of rats. A lower number of n values is due to technical issue in echocardiography data acquisition.

    Journal: PLoS ONE

    Article Title: A G-protein-biased S1P 1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

    doi: 10.1371/journal.pone.0257929

    Figure Lengend Snippet: (A) Heart weight/tibia length, (B) left atrial weight/tibia length, (C) right atrial weight/tibia length, (D) interventricular septum thickness at end-diastole (IVSd), (E) interventricular septum thickness at end-systole (IVSs), (F) left ventricular posterior wall thickness at end-diastole (LVPWd), (G) left ventricular posterior wall thickness at end-systole (LVPWs). Data expressed as mean ± SEM, except IVSd and LVPWd which are expressed as median ± IQR. †† p<0.01, ††† p<0.001: comparison of Le-ZSF1-CTRL to Ob-ZSF1-CTRL using a Student t-test, except LVPWd (adult animals) for which a Wilcoxon test was performed. ‡ p<0.05, ‡‡ p<0.01, ‡‡‡ p<0.001: comparison between Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 using a Student t-test, except LVPWd (adult animals) for which a Wilcoxon test was performed. For adult animals, Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 11 and Ob-ZSF1-SAR247799 N = 10–11. For aged animals Le-ZSF1-CTRL N = 8–9, Ob-ZSF1-CTRL N = 6–7 and Ob-ZSF1-SAR247799 N = 7; N = number of rats. A lower number of n values is due to technical issue in echocardiography data acquisition.

    Article Snippet: Ob-ZSF1 rats were randomized based on the E/e’ value to a control chow diet (Ob-ZSF1-CTRL N = 7) or to a diet with chow supplemented with 0.025% (w/w) SAR247799 (Ob-ZSF1-SAR247799 N = 7), (SSNIFF Spezialdiäten GmbH).

    Techniques:

    (A) perivascular collagen, (B) interstitial collagen, (C) representative histological images of cardiac fibrosis in Le-ZSF1-CTRL (I.), Ob-ZSF1-CTRL (II.) andOb-ZSF1-SAR247799 (III.), scale bar 5 mm and corresponding perivascular fibrosis (IV., V. and V.,) stained in green by Masson trichrome staining, scale bar, 100 μm. (D) microvascular density. Scatter plot showing relationships between (E) perivascular collagen and diastolic dysfunction (E/e’), (F) perivascular collagen and heart weight/ tibia length (normalized cardiac hypertrophy), (G) diastolic dysfunction (E/e’) and heart weight/ tibia length. For (A, B and D) data presented as mean ± SEM. † p<0.05: p-values obtained to compare Le-ZSF1-CTRL to Ob-ZSF1-CTRL using a Student t-test. ‡‡‡ p<0.001: p-values obtained from the comparison between Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 using a Student t-test. Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 7 and Ob-ZSF1-SAR247799 N = 7; N = number of rats.

    Journal: PLoS ONE

    Article Title: A G-protein-biased S1P 1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

    doi: 10.1371/journal.pone.0257929

    Figure Lengend Snippet: (A) perivascular collagen, (B) interstitial collagen, (C) representative histological images of cardiac fibrosis in Le-ZSF1-CTRL (I.), Ob-ZSF1-CTRL (II.) andOb-ZSF1-SAR247799 (III.), scale bar 5 mm and corresponding perivascular fibrosis (IV., V. and V.,) stained in green by Masson trichrome staining, scale bar, 100 μm. (D) microvascular density. Scatter plot showing relationships between (E) perivascular collagen and diastolic dysfunction (E/e’), (F) perivascular collagen and heart weight/ tibia length (normalized cardiac hypertrophy), (G) diastolic dysfunction (E/e’) and heart weight/ tibia length. For (A, B and D) data presented as mean ± SEM. † p<0.05: p-values obtained to compare Le-ZSF1-CTRL to Ob-ZSF1-CTRL using a Student t-test. ‡‡‡ p<0.001: p-values obtained from the comparison between Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 using a Student t-test. Le-ZSF1-CTRL N = 9, Ob-ZSF1-CTRL N = 7 and Ob-ZSF1-SAR247799 N = 7; N = number of rats.

    Article Snippet: Ob-ZSF1 rats were randomized based on the E/e’ value to a control chow diet (Ob-ZSF1-CTRL N = 7) or to a diet with chow supplemented with 0.025% (w/w) SAR247799 (Ob-ZSF1-SAR247799 N = 7), (SSNIFF Spezialdiäten GmbH).

    Techniques: Staining

    A) systolic blood pressure (SBP), (B) diastolic blood pressure, (C) representative spectra of systolic blood pressure variability showing very low frequency (VLF), low frequency (LF) and high frequency (HF) bands. (D) very low frequency (n.u.) bands from spectral analysis of SBP variability. Data presented as mean ± SEM, except SBP who is presented as median ± IQR. * p<0.05, ** p<0.01: p-values obtained to compare Le-ZSF1-CTRL to Ob-ZSF1 (Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 pooled) using a Student t-test. A Student t-test was also performed to compare Ob-ZSF1-CTRL to Ob-ZSF1-SAR247799 at baseline. No significant difference was observed between the two randomized groups at baseline for any of the parameters. † p<0.05: p-values obtained to compare Le-ZSF1-CTRL to Ob-ZSF1-CTRL using a Student t-test. ‡ p<0.05: p-values obtained from the comparison between Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 using a Student t-test except for SBP for which a Wilcoxon test was performed. For adult animals, Le-ZSF1-CTRL N = 8, Ob-ZSF1-CTRL N = 8 and Ob-ZSF1-SAR247799 N = 7; N = number of rats. The lower number of n values is due to technical issue in telemetry data acquisition.

    Journal: PLoS ONE

    Article Title: A G-protein-biased S1P 1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

    doi: 10.1371/journal.pone.0257929

    Figure Lengend Snippet: A) systolic blood pressure (SBP), (B) diastolic blood pressure, (C) representative spectra of systolic blood pressure variability showing very low frequency (VLF), low frequency (LF) and high frequency (HF) bands. (D) very low frequency (n.u.) bands from spectral analysis of SBP variability. Data presented as mean ± SEM, except SBP who is presented as median ± IQR. * p<0.05, ** p<0.01: p-values obtained to compare Le-ZSF1-CTRL to Ob-ZSF1 (Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 pooled) using a Student t-test. A Student t-test was also performed to compare Ob-ZSF1-CTRL to Ob-ZSF1-SAR247799 at baseline. No significant difference was observed between the two randomized groups at baseline for any of the parameters. † p<0.05: p-values obtained to compare Le-ZSF1-CTRL to Ob-ZSF1-CTRL using a Student t-test. ‡ p<0.05: p-values obtained from the comparison between Ob-ZSF1-CTRL and Ob-ZSF1-SAR247799 using a Student t-test except for SBP for which a Wilcoxon test was performed. For adult animals, Le-ZSF1-CTRL N = 8, Ob-ZSF1-CTRL N = 8 and Ob-ZSF1-SAR247799 N = 7; N = number of rats. The lower number of n values is due to technical issue in telemetry data acquisition.

    Article Snippet: Ob-ZSF1 rats were randomized based on the E/e’ value to a control chow diet (Ob-ZSF1-CTRL N = 7) or to a diet with chow supplemented with 0.025% (w/w) SAR247799 (Ob-ZSF1-SAR247799 N = 7), (SSNIFF Spezialdiäten GmbH).

    Techniques:

    Renal function and physiological parameters at baseline and after 4 weeks of treatment.

    Journal: PLoS ONE

    Article Title: A G-protein-biased S1P 1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

    doi: 10.1371/journal.pone.0257929

    Figure Lengend Snippet: Renal function and physiological parameters at baseline and after 4 weeks of treatment.

    Article Snippet: Ob-ZSF1 rats were randomized based on the E/e’ value to a control chow diet (Ob-ZSF1-CTRL N = 7) or to a diet with chow supplemented with 0.025% (w/w) SAR247799 (Ob-ZSF1-SAR247799 N = 7), (SSNIFF Spezialdiäten GmbH).

    Techniques:

    Comparison of the protective effects of SAR247799 in aged obese ZSF1 rats with effects seen in prior experimental systems.

    Journal: PLoS ONE

    Article Title: A G-protein-biased S1P 1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

    doi: 10.1371/journal.pone.0257929

    Figure Lengend Snippet: Comparison of the protective effects of SAR247799 in aged obese ZSF1 rats with effects seen in prior experimental systems.

    Article Snippet: Ob-ZSF1 rats were randomized based on the E/e’ value to a control chow diet (Ob-ZSF1-CTRL N = 7) or to a diet with chow supplemented with 0.025% (w/w) SAR247799 (Ob-ZSF1-SAR247799 N = 7), (SSNIFF Spezialdiäten GmbH).

    Techniques: Concentration Assay, Staining