Your browser doesn't support javascript.
loading
Optimizing Nav1.7-Targeted Analgesics: Revealing Off-Target Effects of Spider Venom-Derived Peptide Toxins and Engineering Strategies for Improvement.
Luo, Sen; Zhou, Xi; Wu, Meijing; Wang, Gongxin; Wang, Li; Feng, Xujun; Wu, Hang; Luo, Ren; Lu, Minjuan; Ju, Junxian; Wang, Wenxing; Yuan, Lei; Luo, Xiaoqing; Peng, Dezheng; Yang, Li; Zhang, Qingfeng; Chen, Minzhi; Liang, Songping; Dong, Xiuming; Hao, Guoliang; Zhang, Yunxiao; Liu, Zhonghua.
Afiliação
  • Luo S; The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • Zhou X; Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, Hunan, 410081, China.
  • Wu M; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
  • Wang G; The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • Wang L; Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, Hunan, 410081, China.
  • Feng X; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
  • Wu H; The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • Luo R; Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, Hunan, 410081, China.
  • Lu M; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
  • Ju J; Henan Academy of Innovations in Medical science, Institute of Electrophysiology, Zhengzhou, Henan, 450000, China.
  • Wang W; The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • Yuan L; Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, Hunan, 410081, China.
  • Luo X; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
  • Peng D; The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • Yang L; Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, Hunan, 410081, China.
  • Zhang Q; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
  • Chen M; The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • Liang S; Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, Hunan, 410081, China.
  • Dong X; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
  • Hao G; The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, China.
  • Zhang Y; Peptide and small molecule drug R&D platform, Furong Laboratory, Hunan Normal University, Changsha, Hunan, 410081, China.
  • Liu Z; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha, 410081, China.
Adv Sci (Weinh) ; : e2406656, 2024 Sep 09.
Article em En | MEDLINE | ID: mdl-39248322
ABSTRACT
The inhibition of Nav1.7 is a promising strategy for the development of analgesic treatments. Spider venom-derived peptide toxins are recognized as significant sources of Nav1.7 inhibitors. However, their development has been impeded by limited selectivity. In this study, eight peptide toxins from three distinct spider venom Nav channel families demonstrated robust inhibition of hNav1.7, rKv4.2, and rKv4.3 (rKv4.2/4.3) currents, exhibiting a similar mode of action. The analysis of structure and function relationship revealed a significant overlap in the pharmacophore responsible for inhibiting hNav1.7 and rKv4.2 by HNTX-III, although Lys25 seems to play a more pivotal role in the inhibition of rKv4.2/4.3. Pharmacophore-guided rational design is employed for the development of an mGpTx1 analogue, mGpTx1-SA, which retains its inhibition of hNav1.7 while significantly reducing its inhibition of rKv4.2/4.3 and eliminating cardiotoxicity. Moreover, mGpTx1-SA demonstrates potent analgesic effects in both inflammatory and neuropathic pain models, accompanied by an improved in vivo safety profile. The results suggest that off-target inhibition of rKv4.2/4.3 by specific spider peptide toxins targeting hNav1.7 may arise from a conserved binding motif. This insight promises to facilitate the design of hNav1.7-specific analgesics, aimed at minimizing rKv4.2/4.3 inhibition and associated toxicity, thereby enhancing their suitability for therapeutic applications.
Palavras-chave
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Adv Sci (Weinh) Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Alemanha
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Adv Sci (Weinh) Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Alemanha