Refining the <scp> Na <sub>V</sub> 1 </scp> .7 pharmacophore of a class of venom‐derived peptide inhibitors <i>via</i> a combination of <i>in silico</i> screening and rational engineering
Ion channels are among the main targets of venom peptides. Extensive functional screening has identified a number of these peptides as modulators of the voltage-gated sodium channel subtype Na<sub>V</sub>1.7, a potential target for the treatment of chronic pain. In this study, we used a bioinformatic approach that can automatically identify Na<sub>V</sub>1.7 gating modifier toxins from sequence information alone. The method further enables the incorporation of evolutionarily accessible sequence space in structure-activity relationship studies. The in silico method identified a putative Na<sub>V</sub>1.7 inhibitor, μ-theraphotoxin Cg4a, which we produced recombinantly and confirmed as a Na<sub>V</sub>1.7 inhibitor. Using structural and mutagenesis studies, we propose an improved definition of the pharmacophore of this class of Na<sub>V</sub>1.7 inhibitors, aiding future in silico screening and classification of Na<sub>V</sub>1.7 inhibitors.
Authors
- Irina Vetter (ORCID: https://orcid.org/0000-0002-3594-9588)
- Theo Crawford (ORCID: https://orcid.org/0000-0002-1101-5705)
- Eivind A. B. Undheim (ORCID: https://orcid.org/0000-0002-8667-3999)
- Mehdi Mobli (ORCID: https://orcid.org/0000-0003-2420-4262)
- Sassan Rahnama
- Gagan Sharma (ORCID: https://orcid.org/0000-0001-5749-007X)
- Jennifer R. Deuis (ORCID: https://orcid.org/0000-0002-5107-8938)
- Xinying Jia
- Yanni K. ‐Y. Chin
Institutions
- The University of Queensland (AU)
- National University of Singapore (SG)
- University of Oslo (NO)
Publication Details
- Journal
- FEBS Letters
- Published
- 2025-03-29
- DOI
- https://doi.org/10.1002/1873-3468.70036
- Primary Topic
- Nicotinic Acetylcholine Receptors Study
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- University of Queensland
- Australian Research Council