Publikation: Mutational analysis of ProTx-I and the novel venom peptide Pe1b provide insight into residues responsible for selective inhibition of the analgesic drug target NaV1.7
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Management of chronic pain presents a major challenge, since many currently available treatments lack efficacy and have problems such as addiction and tolerance. Loss of function mutations in the SCN9A gene lead to a congenital inability to feel pain, with no other sensory deficits aside from anosmia. SCN9A encodes the voltage-gated sodium (NaV) channel 1.7 (NaV1.7), which has been identified as a primary pain target. However, in developing NaV1.7-targeted analgesics, extreme care must to be taken to avoid off-target activity on other NaV subtypes that are critical for survival. Since spider venoms are an excellent source of NaV channel modulators, we screened a panel of spider venoms to identify selective NaV1.7 inhibitors. This led to identification of two novel NaV modulating venom peptides (β/μ-theraphotoxin-Pe1a and β/μ-theraphotoxin-Pe1b (Pe1b) from the arboreal tarantula Phormingochilus everetti. A third peptide isolated from the tarantula Bumba pulcherrimaklaasi was identical to the well-known ProTx-I (β/ω-theraphotoxin-Tp1a) from the tarantula Thrixopelma pruriens. A tethered toxin (t-toxin)-based alanine scanning strategy was used to determine the NaV1.7 pharmacophore of ProTx-I. We designed several ProTx-I and Pe1b analogues, and tested them for activity and NaV channel subtype selectivity. Several analogues had improved potency against NaV1.7, and altered specificity against other NaV channels. These analogues provide a foundation for development of Pe1b as a lead molecule for therapeutic inhibition of NaV1.7.
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RUPASINGHE, Darshani B., Volker HERZIG, Irina VETTER, Zoltan DEKAN, John GILCHRIST, Frank BOSMANS, Paul F. ALEWOOD, Richard J. LEWIS, Glenn F. KING, 2020. Mutational analysis of ProTx-I and the novel venom peptide Pe1b provide insight into residues responsible for selective inhibition of the analgesic drug target NaV1.7. In: Biochemical Pharmacology. Elsevier. 2020, 181, 114080. ISSN 0006-2952. eISSN 1873-2968. Available under: doi: 10.1016/j.bcp.2020.114080BibTex
@article{Rupasinghe2020-11Mutat-51661, year={2020}, doi={10.1016/j.bcp.2020.114080}, title={Mutational analysis of ProTx-I and the novel venom peptide Pe1b provide insight into residues responsible for selective inhibition of the analgesic drug target Na<sub>V</sub>1.7}, volume={181}, issn={0006-2952}, journal={Biochemical Pharmacology}, author={Rupasinghe, Darshani B. and Herzig, Volker and Vetter, Irina and Dekan, Zoltan and Gilchrist, John and Bosmans, Frank and Alewood, Paul F. and Lewis, Richard J. and King, Glenn F.}, note={Article Number: 114080} }
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