Scientific article
Open access

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

Published inJournal of medicinal chemistry, vol. 66, no. 18, p. 13086-13102
Publication date2023-09-13
First online date2023-09-13

Following a rational design, a series of macrocyclic ("stapled") peptidomimetics of10Panx1, the most established peptide inhibitor of Pannexin1 (Panx1) channels, were developed and synthesized. Two macrocyclic analoguesSBL-PX1-42andSBL-PX1-44outperformed the linear native peptide. Duringin vitroadenosine 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 native10Panx1 sequence. The introduction of triazole-based cross-links within the peptide backbones increased helical content and enhancedin vitroproteolytic stability in human plasma (>30-fold longer half-lives, compared to10Panx1). In adhesion assays, a "double-stapled" peptide,SBL-PX1-206inhibited 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 futurein vivoinvestigations in animal models of cardiovascular inflammatory disease.

  • European Commission - Production of next generation modulators of pannexins and connexins as novel therapeutics in the treatment of inflammatory cardiovascular, hepatic and joint diseases. [858014]
Citation (ISO format)
LAMOUROUX, Arthur et al. Structure-Based Design and Synthesis of Stapled 10Panx1 Analogues for Use in Cardiovascular Inflammatory Diseases. In: Journal of medicinal chemistry, 2023, vol. 66, n° 18, p. 13086–13102. doi: 10.1021/acs.jmedchem.3c01116
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ISSN of the journal0022-2623

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