Mambalgin 1, a toxin isolated from black mamba venom, is a disulfide-rich polypeptide consisting of 57 amino acids and belongs to the family of three-finger toxins. It is an effective, rapid, reversible inhibitor of ASIC1a or ASIC1b-containing channels in both central and peripheral neurons. The analgesic effect of mambalgin 1 is as strong as that of morphine, but it does not involve opioid receptors. Compared with traditional opioid drugs, it has fewer side effects and has higher therapeutic value.
The X-ray structure of mambalgin-1 has been solved and consists of a three-finger protein fold in which typically three "finger-like" loops containing beta folds are emitted from a central core stabilized by disulfide bonds.. Structurally, mambalgin 1 is directly integrated with the thumb area of cASIC1a. Mambalgin 1 interacts only with the outer surface of the thumb area of cASIC1a, rather than with an acidic pocket, or with the proposed interfacial region in the beta-ball or palm field. A detailed interface analysis showed that Finger I of mambalgin 1 interact with the α4 helix of the cASIC1a thumb domain. The cassi1a mutants (r316A and y317a) located on the α4 helix also showed different inhibitory responses to manbalgin 1 binding.
Asics is involved in a variety of physiological processes, including synaptic plasticity, neurodegeneration, and pain. As a result, Asics has become a new potential therapeutic target for the treatment of mental illness, neurodegenerative diseases and pain. Mambalgin 1 interacts directly with the thumb domain of cASIC1a but not with the acid-sensing pocket as hypothesized through docking analysis based on cASIC1a–PcTx1 crystal structures. At the same time, mambalgin 1 binding was observed to induce an obvious conformational change in the extracellular thumb domain of cASIC1a, which might disrupt the acid-sensing process in cASIC1a.
Pharmacokinetics and metabolism
Mambalgin 1 has undergone clinical trials and has developed venom-based drugs that inhibit neural pathways involved in pain and other sensory pathways. In laboratory experiments using laboratory mice, mambalgin 1 appears to exert clinically significant analgesic effects without side effects (such as respiratory depression and drug tolerance, both associated with opioid analgesics) typically associated with opioid analgesics.
1. Wemmie, J. A., Taugher, R. J., & Kreple, C. J. (2013). Acid-sensing ion channels in pain and disease. Nature Reviews Neuroscience, 14(7), 461-471.