The road to evolution of ProTx2: how to be a subtype-specific inhibition of human Na_v1.7.

ABSTRACT: The human voltage-gated sodium channel Na_v1.7 is a widely proven target for analgesic drug studies. ProTx2, a 30-residue polypeptide from Peruvian green tarantula venom, shows high specificity to activity against human Na_v1.7, suggesting its potential to become a non-addictive analgesic. However, its high sensitivity to human Na_v1.4 raises concerns about muscle side effects. Here, we engineered three mutants (R13A, R13D, and K27Y) of ProTx2 to evaluate their pharmacological activities toward Na_v1.7 and Na_v1.4. It is demonstrated that the mutant R13D maintained the analgesic effect in mice while dramatically reducing its muscle toxicity compared with ProTx2. The main reason is the formation of a strong electrostatic interaction between

SUBMITTER: Zhao F 

PROVIDER: S-EPMC11096480 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature