Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1

Anne Caufriez; Arthur Lamouroux; Charlotte Martin; Debora Iaculli; Elif Ince Ergüç; Rafael Gozalbes; María Dolores Mayán Santos; Brenda R. Kwak; Andres Tabernilla Garcia; Mathieu Vinken; Steven Ballet

doi:10.1016/j.bioorg.2023.106612

Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1

Anne Caufriez, Arthur Lamouroux, Charlotte Martin, Debora Iaculli, Elif Ince Ergüç, Rafael Gozalbes, María Dolores Mayán Santos, Brenda R. Kwak, Andres Tabernilla Garcia, Mathieu Vinken, Steven Ballet

Research output: Contribution to journal › Article › peer-review

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Abstract

Pannexin1 channels facilitate paracrine communication and are involved in a broad spectrum of diseases. Attempts to find appropriate Pannexin1 channel inhibitors that showcase target-selective properties and in vivo applicability remain nonetheless scarce. However, a promising lead candidate, the ten amino acid long peptide mimetic 10Panx1 (H-Trp1-Arg2-Gln3-Ala4-Ala5-Phe6-Val7-Asp8-Ser9-Tyr10-OH), has shown potential as a Pannexin1 channel inhibitor in both in vitro and in vivo studies. Nonetheless, structural optimization is critical for clinical use. One of the main hurdles to overcome along the optimization process consists of subduing the low biological stability (10Panx1 t1/2 = 2.27 ± 0.11 minutes). To tackle this issue, identification of important structural features within the decapeptide structure is warranted. For this reason, a structure-activity relationship study was performed to proteolytically stabilize the sequence. Through an Alanine scan, this study demonstrated that the side chains of Gln3 and Asp8 are crucial for 10Panx1’s channel inhibitory capacity. Guided by plasma stability experiments, scissile amide bonds were identified and stabilized, while extracellular adenosine triphosphate release experiments, indicative of Pannexin1 channel functionality, allowed to enhance the in vitro inhibitory capacity of 10Panx1.

Original language	English
Article number	106612
Number of pages	8
Journal	Bioorganic Chemistry
Volume	138
DOIs	https://doi.org/10.1016/j.bioorg.2023.106612
Publication status	Published - Sep 2023

Bibliographical note

Funding Information:
S.B., C.M. and M.V. acknowledge the Research Council of the VUB for the financial support through the Strategic Research Program (SRP50). M.V. also received funding from the Methusalem program of the Flemish government. This research has received funding from the European Union’s Horizon 2020 Future and Emerging Technologies program under grant agreement number 858014 (project PANACHE). The authors are grateful to the Rode Kruis Vlaanderen for the supply of human plasma.

Funding Information:
S.B. C.M. and M.V. acknowledge the Research Council of the VUB for the financial support through the Strategic Research Program (SRP50). M.V. also received funding from the Methusalem program of the Flemish government. This research has received funding from the European Union's Horizon 2020 Future and Emerging Technologies program under grant agreement number 858014 (project PANACHE). The authors are grateful to the Rode Kruis Vlaanderen for the supply of human plasma.

Publisher Copyright:
© 2023 The Author(s)

Copyright:
Copyright 2023 Elsevier B.V., All rights reserved.

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10.1016/j.bioorg.2023.106612Licence: CC BY-NC-ND

paperFinal published version, 2.34 MBLicence: CC BY-NC-ND

Cite this

Caufriez, A., Lamouroux, A., Martin, C., Iaculli, D., Ince Ergüç, E., Gozalbes, R., Mayán Santos, M. D., Kwak, B. R., Tabernilla Garcia, A., Vinken, M., & Ballet, S. (2023). Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1. Bioorganic Chemistry, 138, [106612]. https://doi.org/10.1016/j.bioorg.2023.106612

Caufriez, Anne ; Lamouroux, Arthur ; Martin, Charlotte ; Iaculli, Debora ; Ince Ergüç, Elif ; Gozalbes, Rafael ; Mayán Santos, María Dolores ; Kwak, Brenda R. ; Tabernilla Garcia, Andres ; Vinken, Mathieu ; Ballet, Steven. / Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1. In: Bioorganic Chemistry. 2023 ; Vol. 138.

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title = "Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1",

abstract = "Pannexin1 channels facilitate paracrine communication and are involved in a broad spectrum of diseases. Attempts to find appropriate Pannexin1 channel inhibitors that showcase target-selective properties and in vivo applicability remain nonetheless scarce. However, a promising lead candidate, the ten amino acid long peptide mimetic 10Panx1 (H-Trp1-Arg2-Gln3-Ala4-Ala5-Phe6-Val7-Asp8-Ser9-Tyr10-OH), has shown potential as a Pannexin1 channel inhibitor in both in vitro and in vivo studies. Nonetheless, structural optimization is critical for clinical use. One of the main hurdles to overcome along the optimization process consists of subduing the low biological stability (10Panx1 t1/2 = 2.27 ± 0.11 minutes). To tackle this issue, identification of important structural features within the decapeptide structure is warranted. For this reason, a structure-activity relationship study was performed to proteolytically stabilize the sequence. Through an Alanine scan, this study demonstrated that the side chains of Gln3 and Asp8 are crucial for 10Panx1{\textquoteright}s channel inhibitory capacity. Guided by plasma stability experiments, scissile amide bonds were identified and stabilized, while extracellular adenosine triphosphate release experiments, indicative of Pannexin1 channel functionality, allowed to enhance the in vitro inhibitory capacity of 10Panx1. ",

author = "Anne Caufriez and Arthur Lamouroux and Charlotte Martin and Debora Iaculli and {Ince Erg{\"u}{\c c}}, Elif and Rafael Gozalbes and {May{\'a}n Santos}, {Mar{\'i}a Dolores} and Kwak, {Brenda R.} and {Tabernilla Garcia}, Andres and Mathieu Vinken and Steven Ballet",

note = "Funding Information: S.B., C.M. and M.V. acknowledge the Research Council of the VUB for the financial support through the Strategic Research Program (SRP50). M.V. also received funding from the Methusalem program of the Flemish government. This research has received funding from the European Union{\textquoteright}s Horizon 2020 Future and Emerging Technologies program under grant agreement number 858014 (project PANACHE). The authors are grateful to the Rode Kruis Vlaanderen for the supply of human plasma. Funding Information: S.B. C.M. and M.V. acknowledge the Research Council of the VUB for the financial support through the Strategic Research Program (SRP50). M.V. also received funding from the Methusalem program of the Flemish government. This research has received funding from the European Union's Horizon 2020 Future and Emerging Technologies program under grant agreement number 858014 (project PANACHE). The authors are grateful to the Rode Kruis Vlaanderen for the supply of human plasma. Publisher Copyright: {\textcopyright} 2023 The Author(s) Copyright: Copyright 2023 Elsevier B.V., All rights reserved.",

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doi = "10.1016/j.bioorg.2023.106612",

language = "English",

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Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1. / Caufriez, Anne; Lamouroux, Arthur; Martin, Charlotte ; Iaculli, Debora; Ince Ergüç, Elif; Gozalbes, Rafael; Mayán Santos, María Dolores; Kwak, Brenda R.; Tabernilla Garcia, Andres ; Vinken, Mathieu ; Ballet, Steven.

In: Bioorganic Chemistry, Vol. 138, 106612, 09.2023.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1

AU - Caufriez, Anne

AU - Lamouroux, Arthur

AU - Martin, Charlotte

AU - Iaculli, Debora

AU - Ince Ergüç, Elif

AU - Gozalbes, Rafael

AU - Mayán Santos, María Dolores

AU - Kwak, Brenda R.

AU - Tabernilla Garcia, Andres

AU - Vinken, Mathieu

AU - Ballet, Steven

N1 - Funding Information: S.B., C.M. and M.V. acknowledge the Research Council of the VUB for the financial support through the Strategic Research Program (SRP50). M.V. also received funding from the Methusalem program of the Flemish government. This research has received funding from the European Union’s Horizon 2020 Future and Emerging Technologies program under grant agreement number 858014 (project PANACHE). The authors are grateful to the Rode Kruis Vlaanderen for the supply of human plasma. Funding Information: S.B. C.M. and M.V. acknowledge the Research Council of the VUB for the financial support through the Strategic Research Program (SRP50). M.V. also received funding from the Methusalem program of the Flemish government. This research has received funding from the European Union's Horizon 2020 Future and Emerging Technologies program under grant agreement number 858014 (project PANACHE). The authors are grateful to the Rode Kruis Vlaanderen for the supply of human plasma. Publisher Copyright: © 2023 The Author(s) Copyright: Copyright 2023 Elsevier B.V., All rights reserved.

PY - 2023/9

Y1 - 2023/9

N2 - Pannexin1 channels facilitate paracrine communication and are involved in a broad spectrum of diseases. Attempts to find appropriate Pannexin1 channel inhibitors that showcase target-selective properties and in vivo applicability remain nonetheless scarce. However, a promising lead candidate, the ten amino acid long peptide mimetic 10Panx1 (H-Trp1-Arg2-Gln3-Ala4-Ala5-Phe6-Val7-Asp8-Ser9-Tyr10-OH), has shown potential as a Pannexin1 channel inhibitor in both in vitro and in vivo studies. Nonetheless, structural optimization is critical for clinical use. One of the main hurdles to overcome along the optimization process consists of subduing the low biological stability (10Panx1 t1/2 = 2.27 ± 0.11 minutes). To tackle this issue, identification of important structural features within the decapeptide structure is warranted. For this reason, a structure-activity relationship study was performed to proteolytically stabilize the sequence. Through an Alanine scan, this study demonstrated that the side chains of Gln3 and Asp8 are crucial for 10Panx1’s channel inhibitory capacity. Guided by plasma stability experiments, scissile amide bonds were identified and stabilized, while extracellular adenosine triphosphate release experiments, indicative of Pannexin1 channel functionality, allowed to enhance the in vitro inhibitory capacity of 10Panx1.

AB - Pannexin1 channels facilitate paracrine communication and are involved in a broad spectrum of diseases. Attempts to find appropriate Pannexin1 channel inhibitors that showcase target-selective properties and in vivo applicability remain nonetheless scarce. However, a promising lead candidate, the ten amino acid long peptide mimetic 10Panx1 (H-Trp1-Arg2-Gln3-Ala4-Ala5-Phe6-Val7-Asp8-Ser9-Tyr10-OH), has shown potential as a Pannexin1 channel inhibitor in both in vitro and in vivo studies. Nonetheless, structural optimization is critical for clinical use. One of the main hurdles to overcome along the optimization process consists of subduing the low biological stability (10Panx1 t1/2 = 2.27 ± 0.11 minutes). To tackle this issue, identification of important structural features within the decapeptide structure is warranted. For this reason, a structure-activity relationship study was performed to proteolytically stabilize the sequence. Through an Alanine scan, this study demonstrated that the side chains of Gln3 and Asp8 are crucial for 10Panx1’s channel inhibitory capacity. Guided by plasma stability experiments, scissile amide bonds were identified and stabilized, while extracellular adenosine triphosphate release experiments, indicative of Pannexin1 channel functionality, allowed to enhance the in vitro inhibitory capacity of 10Panx1.

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Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1

Abstract

Bibliographical note

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SRP50: SRP-Onderzoekszwaartepunt: Exploiting Peptides: Protein Binders, Modulators and Inhibitors for Imaging and Therapy [Exploit-PeptIT]

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Determination of structural features that underpin the pannexin1 channel inhibitory activity of the peptide 10Panx1

Abstract

Bibliographical note

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Projects

SRP50: SRP-Onderzoekszwaartepunt: Exploiting Peptides: Protein Binders, Modulators and Inhibitors for Imaging and Therapy [Exploit-PeptIT]

Cite this