Engineering Gain-of-Function Analogues of the Spider Venom Peptide HNTX-I, A Potent Blocker of the hNa_V1.7 Sodium Channel.

ABSTRACT: Pain is a medical condition that interferes with normal human life and work and reduces human well-being worldwide. The voltage-gated sodium channel (VGSC) human Na_V1.7 (hNa_V1.7) is a compelling target that plays a key role in human pain signaling. The 33-residue peptide µ-TRTX-Hhn2b (HNTX-I), a member of Na_V-targeting spider toxin (NaSpTx) family 1, has shown negligible activity on mammalian VGSCs, including the hNa_V1.7 channel. We engineered analogues of HNTX-I based on sequence conservation in NaSpTx family 1. Substitution of Asn for Ser at position 23 or Asp for His at position 26 conferred potent activity against hNa_V1.7. Moreover, multiple site mutations combined together afforded improvements in potency. Ultimately, we generated

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC6162447 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature