Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V
Publication Date
May 03, 2018
Authors
Bryan D. Moyer, Justin K. Murray, Joseph Ligutti, Kristin Andrews, et al
Volume
13
Issue
5
Pages
e0196791
DOI
https://dx.plos.org/10.1371/journal.pone.0196791
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0196791
Scopus
85046639014
Mendeley
http://www.mendeley.com/research/pharmacological-characterization-potent-selective-nav17-inhibitors-engineered-chilobrachys-jingzhao
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Mendeley | Further Information

{"title"=>"Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V", "type"=>"journal", "authors"=>[{"first_name"=>"Bryan D.", "last_name"=>"Moyer"}, {"first_name"=>"Justin K.", "last_name"=>"Murray"}, {"first_name"=>"Joseph", "last_name"=>"Ligutti"}, {"first_name"=>"Kristin", "last_name"=>"Andrews"}, {"first_name"=>"Philippe", "last_name"=>"Favreau"}, {"first_name"=>"John B.", "last_name"=>"Jordan"}, {"first_name"=>"Josie H.", "last_name"=>"Lee"}, {"first_name"=>"Dong", "last_name"=>"Liu"}, {"first_name"=>"Jason", "last_name"=>"Long"}, {"first_name"=>"Kelvin", "last_name"=>"Sham"}, {"first_name"=>"Licheng", "last_name"=>"Shi"}, {"first_name"=>"Reto", "last_name"=>"Stöcklin"}, {"first_name"=>"Bin", "last_name"=>"Wu"}, {"first_name"=>"Ruoyuan", "last_name"=>"Yin"}, {"first_name"=>"Violeta", "last_name"=>"Yu"}, {"first_name"=>"Anruo", "last_name"=>"Zou"}, {"first_name"=>"Kaustav", "last_name"=>"Biswas"}, {"first_name"=>"Les P.", "last_name"=>"Miranda"}], "year"=>2018, "source"=>"PLOS ONE", "identifiers"=>{"doi"=>"10.1371/journal.pone.0196791", "issn"=>"1932-6203", "isbn"=>"1111111111"}, "id"=>"90cf4069-2696-377b-8751-a2acb9dc9407", "abstract"=>"Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C-fibers.", "link"=>"http://www.mendeley.com/research/pharmacological-characterization-potent-selective-nav17-inhibitors-engineered-chilobrachys-jingzhao", "reader_count"=>3, "reader_count_by_academic_status"=>{"Researcher"=>2, "Other"=>1}, "reader_count_by_user_role"=>{"Researcher"=>2, "Other"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Chemistry"=>{"Chemistry"=>1}, "Unspecified"=>{"Unspecified"=>2}}, "group_count"=>0}

Scopus | Further Information

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