Design, synthesis, and mechanism of action of novel μ-conotoxin KIIIA analogues for inhibition of the voltage-gated sodium channel Na_v1.7.

ABSTRACT: μ-Conotoxin KIIIA, a selective blocker of sodium channels, has strong inhibitory activity against several Na_v isoforms, including Na_v1.7, and has potent analgesic effects, but it contains three pairs of disulfide bonds, making structural modification difficult and synthesis complex. To circumvent these difficulties, we designed and synthesized three KIIIA analogues with one disulfide bond deleted. The most active analogue, KIIIA-1, was further analyzed, and its binding pattern to hNa_v1.7 was determined by molecular dynamics simulations. Guided by the molecular dynamics computational model, we designed and tested 32 second-generation and 6 third-generation analogues of KIIIA-1 on hNa_v1.7 expressed in HEK293 cells. Several analogues showed signific

SUBMITTER: Zhao Z 

PROVIDER: S-EPMC10074208 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature