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

Darshani B Rupasinghe; Volker Herzig; Irina Vetter; Zoltan Dekan; John Gilchrist; Frank Bosmans; Paul F Alewood; Richard J Lewis; Glenn F King

doi:10.1016/j.bcp.2020.114080

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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

Journal article

Peer reviewed

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

Darshani B Rupasinghe, Volker Herzig, Irina Vetter, Zoltan Dekan, John Gilchrist, Frank Bosmans, Paul F Alewood, Richard J Lewis and Glenn F King

Biochemical Pharmacology, Vol.181, pp.1-16

2020

DOI: https://doi.org/10.1016/j.bcp.2020.114080

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Abstract

Spider-venom peptide

Electrophysiology

Tethered toxin

Analgesic

Peptide pharmacophore

Voltage-gated sodium channel

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.

Details

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
Authors: Darshani B Rupasinghe (Author) - The University of Queensland
Volker Herzig (Author) - The University of Queensland
Irina Vetter (Author) - The University of Queensland
Zoltan Dekan (Author) - The University of Queensland
John Gilchrist (Author) - Johns Hopkins University
Frank Bosmans (Author) - Johns Hopkins University
Paul F Alewood (Author) - The University of Queensland
Richard J Lewis (Author) - The University of Queensland
Glenn F King (Author) - The University of Queensland
Publication details: Biochemical Pharmacology, Vol.181, pp.1-16
Publisher: Elsevier Inc.
Date published: 2020
DOI: 10.1016/j.bcp.2020.114080
ISSN: 1873-2968
Grants: Discovery and development of better pain treatments, 1072113, National Health and Medical Research Council (Australia, Canberra) - NHMRC
Australian Government Research Training Program (RTP) Scholarship, RTP, Department of Education (Australia, Canberra)
Development of potent and specific modulators of the human sodium channel Nav1.7, DP110103129, Australian Research Council (Australia, Canberra) - ARC
Organisation Unit: School of Science and Engineering - Legacy; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99483602902621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Pharmacology & Pharmacy

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