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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

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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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. 181, 114080. ISSN 0006-2952. eISSN 1873-2968. Available under: doi: 10.1016/j.bcp.2020.114080

@article{Rupasinghe2020-11Mutat-51661, 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 NaV1.7}, year={2020}, doi={10.1016/j.bcp.2020.114080}, 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} }

Alewood, Paul F. Bosmans, Frank 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 (Na<sub>V</sub>) channel 1.7 (Na<sub>V</sub>1.7), which has been identified as a primary pain target. However, in developing Na<sub>V</sub>1.7-targeted analgesics, extreme care must to be taken to avoid off-target activity on other Na<sub>V</sub> subtypes that are critical for survival. Since spider venoms are an excellent source of Na<sub>V</sub> channel modulators, we screened a panel of spider venoms to identify selective Na<sub>V</sub>1.7 inhibitors. This led to identification of two novel Na<sub>V</sub> 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 Na<sub>V</sub>1.7 pharmacophore of ProTx-I. We designed several ProTx-I and Pe1b analogues, and tested them for activity and Na<sub>V</sub> channel subtype selectivity. Several analogues had improved potency against Na<sub>V</sub>1.7, and altered specificity against other Na<sub>V</sub> channels. These analogues provide a foundation for development of Pe1b as a lead molecule for therapeutic inhibition of Na<sub>V</sub>1.7. King, Glenn F. 2020-11-05T08:52:16Z Herzig, Volker 2020-11 Vetter, Irina 2020-11-05T08:52:16Z Gilchrist, John 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 eng Lewis, Richard J. Vetter, Irina Alewood, Paul F. King, Glenn F. Lewis, Richard J. Rupasinghe, Darshani B. Dekan, Zoltan Bosmans, Frank Gilchrist, John Rupasinghe, Darshani B. Dekan, Zoltan Herzig, Volker

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