Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases

Arthur Lamouroux; Malaury Tournier; Debora Iaculli; Anne Caufriez; Olga M Rusiecka; Charlotte Martin; Viviane Bes; Laureano E Carpio; Yana Girardin; Remy Loris; Andrés Tabernilla; Filippo Molica; Rafael Gozalbes; María D Mayán; Mathieu Vinken; Brenda R Kwak; Steven Ballet

doi:10.1021/acs.jmedchem.3c01116

Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases

Arthur Lamouroux, Malaury Tournier, Debora Iaculli, Anne Caufriez, Olga M Rusiecka, Charlotte Martin, Viviane Bes, Laureano E Carpio, Yana Girardin, Remy Loris, Andrés Tabernilla, Filippo Molica, Rafael Gozalbes, María D Mayán, Mathieu Vinken, Brenda R Kwak, Steven Ballet

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Abstract

Following a rational design, a series of macrocyclic ("stapled") peptidomimetics of 10Panx1, the most established peptide inhibitor of Pannexin1 (Panx1) channels, were developed and synthesized. Two macrocyclic analogues SBL-PX1-42 and SBL-PX1-44 outperformed the linear native peptide. During in vitro adenosine triphosphate (ATP) release and Yo-Pro-1 uptake assays in a Panx1-expressing tumor cell line, both compounds were revealed to be promising bidirectional inhibitors of Panx1 channel function, able to induce a two-fold inhibition, as compared to the native 10Panx1 sequence. The introduction of triazole-based cross-links within the peptide backbones increased helical content and enhanced in vitro proteolytic stability in human plasma (>30-fold longer half-lives, compared to 10Panx1). In adhesion assays, a "double-stapled" peptide, SBL-PX1-206 inhibited ATP release from endothelial cells, thereby efficiently reducing THP-1 monocyte adhesion to a TNF-α-activated endothelial monolayer and making it a promising candidate for future in vivo investigations in animal models of cardiovascular inflammatory disease.

Original language	English
Pages (from-to)	13086-13102
Number of pages	17
Journal	Journal of medicinal chemistry
Volume	66
Issue number	18
DOIs	https://doi.org/10.1021/acs.jmedchem.3c01116
Publication status	Published - 28 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). 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.

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Lamouroux, A., Tournier, M., Iaculli, D., Caufriez, A., Rusiecka, O. M., Martin, C., Bes, V., Carpio, L. E., Girardin, Y., Loris, R., Tabernilla, A., Molica, F., Gozalbes, R., Mayán, M. D., Vinken, M., Kwak, B. R., & Ballet, S. (2023). Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases. Journal of medicinal chemistry, 66(18), 13086-13102. https://doi.org/10.1021/acs.jmedchem.3c01116

Lamouroux, Arthur ; Tournier, Malaury ; Iaculli, Debora ; Caufriez, Anne ; Rusiecka, Olga M ; Martin, Charlotte ; Bes, Viviane ; Carpio, Laureano E ; Girardin, Yana ; Loris, Remy ; Tabernilla, Andrés ; Molica, Filippo ; Gozalbes, Rafael ; Mayán, María D ; Vinken, Mathieu ; Kwak, Brenda R ; Ballet, Steven. / Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases. In: Journal of medicinal chemistry. 2023 ; Vol. 66, No. 18. pp. 13086-13102.

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title = "Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases",

abstract = "Following a rational design, a series of macrocyclic ({"}stapled{"}) peptidomimetics of 10Panx1, the most established peptide inhibitor of Pannexin1 (Panx1) channels, were developed and synthesized. Two macrocyclic analogues SBL-PX1-42 and SBL-PX1-44 outperformed the linear native peptide. During in vitro adenosine triphosphate (ATP) release and Yo-Pro-1 uptake assays in a Panx1-expressing tumor cell line, both compounds were revealed to be promising bidirectional inhibitors of Panx1 channel function, able to induce a two-fold inhibition, as compared to the native 10Panx1 sequence. The introduction of triazole-based cross-links within the peptide backbones increased helical content and enhanced in vitro proteolytic stability in human plasma (>30-fold longer half-lives, compared to 10Panx1). In adhesion assays, a {"}double-stapled{"} peptide, SBL-PX1-206 inhibited ATP release from endothelial cells, thereby efficiently reducing THP-1 monocyte adhesion to a TNF-α-activated endothelial monolayer and making it a promising candidate for future in vivo investigations in animal models of cardiovascular inflammatory disease.",

author = "Arthur Lamouroux and Malaury Tournier and Debora Iaculli and Anne Caufriez and Rusiecka, {Olga M} and Charlotte Martin and Viviane Bes and Carpio, {Laureano E} and Yana Girardin and Remy Loris and Andr{\'e}s Tabernilla and Filippo Molica and Rafael Gozalbes and May{\'a}n, {Mar{\'i}a D} and Mathieu Vinken and Kwak, {Brenda R} 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). 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.",

year = "2023",

month = sep,

day = "28",

doi = "10.1021/acs.jmedchem.3c01116",

language = "English",

volume = "66",

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journal = "Journal of Medicinal Chemistry",

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Lamouroux, A, Tournier, M, Iaculli, D , Caufriez, A, Rusiecka, OM, Martin, C, Bes, V, Carpio, LE, Girardin, Y , Loris, R , Tabernilla, A, Molica, F, Gozalbes, R, Mayán, MD, Vinken, M, Kwak, BR & Ballet, S 2023, 'Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases', Journal of medicinal chemistry, vol. 66, no. 18, pp. 13086-13102. https://doi.org/10.1021/acs.jmedchem.3c01116

Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases. / Lamouroux, Arthur; Tournier, Malaury; Iaculli, Debora ; Caufriez, Anne; Rusiecka, Olga M; Martin, Charlotte; Bes, Viviane; Carpio, Laureano E; Girardin, Yana ; Loris, Remy ; Tabernilla, Andrés; Molica, Filippo; Gozalbes, Rafael; Mayán, María D; Vinken, Mathieu; Kwak, Brenda R; Ballet, Steven.

In: Journal of medicinal chemistry, Vol. 66, No. 18, 28.09.2023, p. 13086-13102.

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

TY - JOUR

T1 - Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases

AU - Lamouroux, Arthur

AU - Tournier, Malaury

AU - Iaculli, Debora

AU - Caufriez, Anne

AU - Rusiecka, Olga M

AU - Martin, Charlotte

AU - Bes, Viviane

AU - Carpio, Laureano E

AU - Girardin, Yana

AU - Loris, Remy

AU - Tabernilla, Andrés

AU - Molica, Filippo

AU - Gozalbes, Rafael

AU - Mayán, María D

AU - Vinken, Mathieu

AU - Kwak, Brenda R

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). 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.

PY - 2023/9/28

Y1 - 2023/9/28

N2 - Following a rational design, a series of macrocyclic ("stapled") peptidomimetics of 10Panx1, the most established peptide inhibitor of Pannexin1 (Panx1) channels, were developed and synthesized. Two macrocyclic analogues SBL-PX1-42 and SBL-PX1-44 outperformed the linear native peptide. During in vitro adenosine triphosphate (ATP) release and Yo-Pro-1 uptake assays in a Panx1-expressing tumor cell line, both compounds were revealed to be promising bidirectional inhibitors of Panx1 channel function, able to induce a two-fold inhibition, as compared to the native 10Panx1 sequence. The introduction of triazole-based cross-links within the peptide backbones increased helical content and enhanced in vitro proteolytic stability in human plasma (>30-fold longer half-lives, compared to 10Panx1). In adhesion assays, a "double-stapled" peptide, SBL-PX1-206 inhibited ATP release from endothelial cells, thereby efficiently reducing THP-1 monocyte adhesion to a TNF-α-activated endothelial monolayer and making it a promising candidate for future in vivo investigations in animal models of cardiovascular inflammatory disease.

AB - Following a rational design, a series of macrocyclic ("stapled") peptidomimetics of 10Panx1, the most established peptide inhibitor of Pannexin1 (Panx1) channels, were developed and synthesized. Two macrocyclic analogues SBL-PX1-42 and SBL-PX1-44 outperformed the linear native peptide. During in vitro adenosine triphosphate (ATP) release and Yo-Pro-1 uptake assays in a Panx1-expressing tumor cell line, both compounds were revealed to be promising bidirectional inhibitors of Panx1 channel function, able to induce a two-fold inhibition, as compared to the native 10Panx1 sequence. The introduction of triazole-based cross-links within the peptide backbones increased helical content and enhanced in vitro proteolytic stability in human plasma (>30-fold longer half-lives, compared to 10Panx1). In adhesion assays, a "double-stapled" peptide, SBL-PX1-206 inhibited ATP release from endothelial cells, thereby efficiently reducing THP-1 monocyte adhesion to a TNF-α-activated endothelial monolayer and making it a promising candidate for future in vivo investigations in animal models of cardiovascular inflammatory disease.

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U2 - 10.1021/acs.jmedchem.3c01116

DO - 10.1021/acs.jmedchem.3c01116

M3 - Article

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VL - 66

SP - 13086

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -

Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases

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