Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation.

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. Copyright © 2021 Elsevier Ltd. All rights reserved.

Citation

Daisuke Asai, Naoko Inoue, Makiko Sugiyama, Tsugumi Fujita, Yutaka Matsuyama, Xiaohui Liu, Ayami Matsushima, Takeru Nose, Tommaso Costa, Yasuyuki Shimohigashi. Direct evidence of edge-to-face CH/π interaction for PAR-1 thrombin receptor activation. Bioorganic & medicinal chemistry. 2021 Dec 01;51:116498

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PMID: 34794000

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