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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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.
Originele taal-2English
Pagina's (van-tot)13086-13102
Aantal pagina's17
TijdschriftJournal of medicinal chemistry
Volume66
Nummer van het tijdschrift18
DOI's
StatusPublished - 28 sep 2023

Bibliografische nota

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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