Journal article
Seven novel modulators of the analgesic target NaV1.7 uncovered using a high-throughput venom-based discovery approach
British Journal of Pharmacology, Vol.172(10), pp.2445-2458
2015
Abstract
Background and Purpose Chronic pain is a serious worldwide health issue, with current analgesics having limited efficacy and dose-limiting side effects. Humans with loss-of-function mutations in the voltage-gated sodium channel NaV1.7 (hNaV1.7) are indifferent to pain, making hNaV1.7 a promising target for analgesic development. Since spider venoms are replete with NaV channel modulators, we examined their potential as a source of hNaV1.7 inhibitors. Experimental Approach We developed a high-throughput fluorescent-based assay to screen spider venoms against hNaV1.7 and isolate 'hit' peptides. To examine the binding site of these peptides, we constructed a panel of chimeric channels in which the S3b-S4 paddle motif from each voltage sensor domain of hNaV1.7 was transplanted into the homotetrameric KV2.1 channel. Key Results We screened 205 spider venoms and found that 40% contain at least one inhibitor of hNaV1.7. By deconvoluting 'hit' venoms, we discovered seven novel members of the NaSpTx family 1. One of these peptides, Hd1a (peptide μ-TRTX-Hd1a from venom of the spider Haplopelma doriae), inhibited hNaV1.7 with a high level of selectivity over all other subtypes, except hNaV1.1. We showed that Hd1a is a gating modifier that inhibits hNaV1.7 by interacting with the S3b-S4 paddle motif in channel domain II. The structure of Hd1a, determined using heteronuclear NMR, contains an inhibitor cystine knot motif that is likely to confer high levels of chemical, thermal and biological stability. Conclusion and Implications Our data indicate that spider venoms are a rich natural source of hNaV1.7 inhibitors that might be useful leads for the development of novel analgesics.
Details
- Title
- Seven novel modulators of the analgesic target NaV1.7 uncovered using a high-throughput venom-based discovery approach
- Authors
- J K Klint (Author) - University of QueenslandJ J Smith (Author) - University of QueenslandI Vetter (Author) - University of QueenslandD B Rupasinghe (Author) - University of QueenslandS Y Er (Author) - University of QueenslandS Senff (Author) - University of QueenslandVolker Herzig (Author) - University of QueenslandM Mobli (Author) - University of QueenslandR J Lewis (Author) - University of QueenslandF Bosmans (Author) - Johns Hopkins University, United StatesG F King (Author) - University of Queensland
- Publication details
- British Journal of Pharmacology, Vol.172(10), pp.2445-2458
- Publisher
- John Wiley & Sons Ltd.
- Date published
- 2015
- DOI
- 10.1111/bph.13081
- ISSN
- 0007-1188
- Organisation Unit
- School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99451106402621
- Output Type
- Journal article
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