Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation
Daisuke Asai, Naoko Inoue, Makiko Sugiyama, Tsugumi Fujita, Yutaka Matsuyama, Xiaohui Liu, Ayami Matsushima, Takeru Nose, Tommaso Costa, Yasuyuki Shimohigashi
Organic and Biological Chemistry
Division for Experimental Natural Science
Heptapeptide SFLLRNP is a receptor–tethered ligand of protease-activated receptor 1 (PAR-1), and its Phe at position 2 is essential for the aggregation of human platelets. To validate the structural elements of the Phe-phenyl group in receptor activation, we have synthesized a complete set of S/Phe/LLRNP peptides comprising different series of fluorophenylalanine isomers (Fn)Phe, where n = 1, 2, 3, and 5. Phe-2-phenyl was strongly suggested to be involved in the edge-to-face CH/π interaction with the receptor aromatic group. In the present study, to prove this receptor interaction definitively, we synthesized another series of peptide analogs containing (F4)Phe-isomers, with the phenyl group of each isomer possessing only one hydrogen atom at the ortho, meta, or para position. When the peptides were assayed for their platelet aggregation activity, S/(2,3,4,6-F4)Phe/LLRNP and S/(2,3,4,5-F4)Phe/LLRNP exhibited noticeable activity (34% and 6% intensities of the native peptide, respectively), whereas S/(2,3,5,6-F4)Phe/LLRNP was completely inactive. The results indicated that, at the ortho and meta positions but not at the para position, benzene-hydrogen atoms are required for the CH/π interaction to activate the receptor. The results provided a decisive evidence of the molecular recognition property of Phe, the phenyl benzene-hydrogen atom of which participates directly in the interaction with the receptor aromatic π plane.
Bioorganic and Medicinal Chemistry
https://doi.org/10.1016/j.bmc.2021.116498
10.1016/j.bmc.2021.116498
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Receptor Pharmacology, Toxicology and Pharmaceutical Science 100%
Eicosanoid Receptor Neuroscience 100%
Peptide Chemistry 80%
Position Biochemistry, Genetics and Molecular Biology 80%
Compound Isomer Chemistry 60%
Hydrogen Atom Chemistry 60%
Hydrogen Pharmacology, Toxicology and Pharmaceutical Science 60%
Isomer Biochemistry, Genetics and Molecular Biology 60%
Asai, D., Inoue, N., Sugiyama, M., Fujita, T., Matsuyama, Y., Liu, X., Matsushima, A., Nose, T., Costa, T., & Shimohigashi, Y. (2021). Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation. Bioorganic and Medicinal Chemistry, 51, [116498]. https://doi.org/10.1016/j.bmc.2021.116498
Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation. / Asai, Daisuke; Inoue, Naoko; Sugiyama, Makiko et al.
In: Bioorganic and Medicinal Chemistry, Vol. 51, 116498, 01.12.2021.
Asai, D, Inoue, N, Sugiyama, M, Fujita, T, Matsuyama, Y, Liu, X, Matsushima, A, Nose, T, Costa, T & Shimohigashi, Y 2021, 'Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation', Bioorganic and Medicinal Chemistry, vol. 51, 116498. https://doi.org/10.1016/j.bmc.2021.116498
Asai D, Inoue N, Sugiyama M, Fujita T, Matsuyama Y, Liu X et al. Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation. Bioorganic and Medicinal Chemistry. 2021 Dec 1;51:116498. doi: 10.1016/j.bmc.2021.116498
Asai, Daisuke ; Inoue, Naoko ; Sugiyama, Makiko et al. / Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation. In: Bioorganic and Medicinal Chemistry. 2021 ; Vol. 51.
@article{a3309fbdad2b4742bd72bcebc33ff9aa,
title = "Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation",
abstract = "Heptapeptide SFLLRNP is a receptor–tethered ligand of protease-activated receptor 1 (PAR-1), and its Phe at position 2 is essential for the aggregation of human platelets. To validate the structural elements of the Phe-phenyl group in receptor activation, we have synthesized a complete set of S/Phe/LLRNP peptides comprising different series of fluorophenylalanine isomers (Fn)Phe, where n = 1, 2, 3, and 5. Phe-2-phenyl was strongly suggested to be involved in the edge-to-face CH/π interaction with the receptor aromatic group. In the present study, to prove this receptor interaction definitively, we synthesized another series of peptide analogs containing (F4)Phe-isomers, with the phenyl group of each isomer possessing only one hydrogen atom at the ortho, meta, or para position. When the peptides were assayed for their platelet aggregation activity, S/(2,3,4,6-F4)Phe/LLRNP and S/(2,3,4,5-F4)Phe/LLRNP exhibited noticeable activity (34% and 6% intensities of the native peptide, respectively), whereas S/(2,3,5,6-F4)Phe/LLRNP was completely inactive. The results indicated that, at the ortho and meta positions but not at the para position, benzene-hydrogen atoms are required for the CH/π interaction to activate the receptor. The results provided a decisive evidence of the molecular recognition property of Phe, the phenyl benzene-hydrogen atom of which participates directly in the interaction with the receptor aromatic π plane.",
author = "Daisuke Asai and Naoko Inoue and Makiko Sugiyama and Tsugumi Fujita and Yutaka Matsuyama and Xiaohui Liu and Ayami Matsushima and Takeru Nose and Tommaso Costa and Yasuyuki Shimohigashi",
note = "Funding Information: We greatly appreciate Dr. Futoshi Kuribayashi of the School of Medicine, Kyushu University, for his kindness in collecting the blood samples. This work was supported by a Japan Society for the Promotion of Science (JSPS) KAKENHI grant (no. JP10480152, to Y.S.). This work was also supported in part by a Health and Labour Sciences Research Grant for Research on the Risk of Chemical Substances from the Ministry of Health, Labour and Welfare of Japan, under contract/grant no. H20-Chemistry-General-003 (to Y.S.). Publisher Copyright: {\textcopyright} 2021",
doi = "10.1016/j.bmc.2021.116498",
journal = "Bioorganic and Medicinal Chemistry",
T1 - Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation
AU - Asai, Daisuke
AU - Inoue, Naoko
AU - Sugiyama, Makiko
AU - Fujita, Tsugumi
AU - Matsuyama, Yutaka
AU - Liu, Xiaohui
AU - Matsushima, Ayami
AU - Nose, Takeru
AU - Costa, Tommaso
AU - Shimohigashi, Yasuyuki
N1 - Funding Information: We greatly appreciate Dr. Futoshi Kuribayashi of the School of Medicine, Kyushu University, for his kindness in collecting the blood samples. This work was supported by a Japan Society for the Promotion of Science (JSPS) KAKENHI grant (no. JP10480152, to Y.S.). This work was also supported in part by a Health and Labour Sciences Research Grant for Research on the Risk of Chemical Substances from the Ministry of Health, Labour and Welfare of Japan, under contract/grant no. H20-Chemistry-General-003 (to Y.S.). Publisher Copyright: © 2021
N2 - Heptapeptide SFLLRNP is a receptor–tethered ligand of protease-activated receptor 1 (PAR-1), and its Phe at position 2 is essential for the aggregation of human platelets. To validate the structural elements of the Phe-phenyl group in receptor activation, we have synthesized a complete set of S/Phe/LLRNP peptides comprising different series of fluorophenylalanine isomers (Fn)Phe, where n = 1, 2, 3, and 5. Phe-2-phenyl was strongly suggested to be involved in the edge-to-face CH/π interaction with the receptor aromatic group. In the present study, to prove this receptor interaction definitively, we synthesized another series of peptide analogs containing (F4)Phe-isomers, with the phenyl group of each isomer possessing only one hydrogen atom at the ortho, meta, or para position. When the peptides were assayed for their platelet aggregation activity, S/(2,3,4,6-F4)Phe/LLRNP and S/(2,3,4,5-F4)Phe/LLRNP exhibited noticeable activity (34% and 6% intensities of the native peptide, respectively), whereas S/(2,3,5,6-F4)Phe/LLRNP was completely inactive. The results indicated that, at the ortho and meta positions but not at the para position, benzene-hydrogen atoms are required for the CH/π interaction to activate the receptor. The results provided a decisive evidence of the molecular recognition property of Phe, the phenyl benzene-hydrogen atom of which participates directly in the interaction with the receptor aromatic π plane.
AB - Heptapeptide SFLLRNP is a receptor–tethered ligand of protease-activated receptor 1 (PAR-1), and its Phe at position 2 is essential for the aggregation of human platelets. To validate the structural elements of the Phe-phenyl group in receptor activation, we have synthesized a complete set of S/Phe/LLRNP peptides comprising different series of fluorophenylalanine isomers (Fn)Phe, where n = 1, 2, 3, and 5. Phe-2-phenyl was strongly suggested to be involved in the edge-to-face CH/π interaction with the receptor aromatic group. In the present study, to prove this receptor interaction definitively, we synthesized another series of peptide analogs containing (F4)Phe-isomers, with the phenyl group of each isomer possessing only one hydrogen atom at the ortho, meta, or para position. When the peptides were assayed for their platelet aggregation activity, S/(2,3,4,6-F4)Phe/LLRNP and S/(2,3,4,5-F4)Phe/LLRNP exhibited noticeable activity (34% and 6% intensities of the native peptide, respectively), whereas S/(2,3,5,6-F4)Phe/LLRNP was completely inactive. The results indicated that, at the ortho and meta positions but not at the para position, benzene-hydrogen atoms are required for the CH/π interaction to activate the receptor. The results provided a decisive evidence of the molecular recognition property of Phe, the phenyl benzene-hydrogen atom of which participates directly in the interaction with the receptor aromatic π plane.
U2 - 10.1016/j.bmc.2021.116498
DO - 10.1016/j.bmc.2021.116498
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry