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; Maria D Mayan; Brenda R Kwak; Andrés Tabernilla; 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

Bioorg Chem. 2023 Sep:138:106612. doi: 10.1016/j.bioorg.2023.106612. Epub 2023 May 15.

Authors

Affiliations

¹ Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; Research Group of In Vitro Toxicology and Dermato-cosmetology, Department of Pharmaceutical and Pharmacological sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
² Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
³ Research Group of In Vitro Toxicology and Dermato-cosmetology, Department of Pharmaceutical and Pharmacological sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
⁴ ProtoQSAR SL, Centro Europeo de Empresas Innovadoras, Parque Tecnológico de Valencia, Avda. Benjamin Franklin 12, 46980 Paterna, Spain.
⁵ CellCOM Research Group, Instituto de Investigación Biomédica de A Coruña, Servizo Galego de Saúde, Universidade da Coruña, 15071 A Coruña, Spain.
⁶ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, 1211 Geneva, Switzerland.
⁷ Research Group of Organic Chemistry, Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium. Electronic address: steven.ballet@vub.be.

PMID: 37210827
DOI: 10.1016/j.bioorg.2023.106612

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 t_1/2 = 2.27 ± 0.11 min). 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.

Keywords: (10)Panx1; Pannexin1 channel inhibition; Plasma stability; Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alanine
Amino Acid Sequence
Amino Acids
Peptide Fragments*
Peptides* / pharmacology

Substances

Peptide Fragments
Peptides
Amino Acids
Alanine