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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 NaV1.7.
Biochem Pharmacol. 2020 11; 181:114080.BP

Abstract

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.

Authors+Show Affiliations

Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address: darshani.rupasinghe@gmail.com.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4105, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address: glenn.king@imb.uq.edu.au.

Pub Type(s)

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

Language

eng

PubMed ID

32511987

Citation

Rupasinghe, Darshani B., et al. "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." Biochemical Pharmacology, vol. 181, 2020, p. 114080.
Rupasinghe DB, Herzig V, Vetter I, et al. 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. Biochem Pharmacol. 2020;181:114080.
Rupasinghe, D. B., Herzig, V., Vetter, I., Dekan, Z., Gilchrist, J., Bosmans, F., Alewood, P. F., Lewis, R. J., & King, G. F. (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. Biochemical Pharmacology, 181, 114080. https://doi.org/10.1016/j.bcp.2020.114080
Rupasinghe DB, et al. 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. Biochem Pharmacol. 2020;181:114080. PubMed PMID: 32511987.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Rupasinghe,Darshani B, AU - Herzig,Volker, AU - Vetter,Irina, AU - Dekan,Zoltan, AU - Gilchrist,John, AU - Bosmans,Frank, AU - Alewood,Paul F, AU - Lewis,Richard J, AU - King,Glenn F, Y1 - 2020/06/06/ PY - 2020/03/31/received PY - 2020/05/30/revised PY - 2020/06/03/accepted PY - 2020/6/9/pubmed PY - 2021/1/5/medline PY - 2020/6/9/entrez KW - Analgesic KW - Electrophysiology KW - Peptide pharmacophore KW - Spider-venom peptide KW - Tethered toxin KW - Voltage-gated sodium channel SP - 114080 EP - 114080 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 181 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/32511987/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(20)30314-2 DB - PRIME DP - Unbound Medicine ER -