2. Academic Validation
  3. 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

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 Nov:181:114080. doi: 10.1016/j.bcp.2020.114080.
Darshani B Rupasinghe 1,  Volker Herzig 2,  Irina Vetter 3,  Zoltan Dekan 2,  John Gilchrist 4,  Frank Bosmans 4,  Paul F Alewood 2,  Richard J Lewis 2,  Glenn F King 5
Affiliations

Affiliations

  • 1 Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address: [email protected].
  • 2 Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
  • 3 Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4105, Australia.
  • 4 Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 5 Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia. Electronic address: [email protected].
PMID: 32511987 DOI: 10.1016/j.bcp.2020.114080
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.

Keywords

Analgesic; Electrophysiology; Peptide pharmacophore; Spider-venom peptide; Tethered toxin; Voltage-gated sodium channel.

Figures
Products