BOC Sciences provides various cytotoxin used as payloads to conjugate with antibodies and form ADCs. Virtually, voltage-gated sodium (Na+) channels are expressed in all electrically excitable tissues and are essential for muscle contraction, and conduction of impulses within the peripheral as well as central nervous systems. Genetic disorders that disrupt the function of voltage-gated sodium (Na+) channels produce a Na+ channelopathies array resulting in cardiac arrhythmias, neuromuscular pathologies and neuronal impairment. Because of their importance to the conduction of electrical signals, Na+ channels are the target of a wide variety of anticancer drugs, local anesthetic and antidepressant drugs.
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The voltage-gated Na+ channels are composed of α-subunits that encode for the voltage sensor domains and the Na+-selective permeation pore. In vivo, Na+ channel α-subunits are associated with one or more accessory β-subunits (β1-β4) that regulate cell-surface expression, trafficking, and gating properties of the channels. Depending on the physical properties of the drug, Na+ channel inhibition can occur by a simple pore-blocking mechanism, or by preferential binding to and stabilization of the channels in nonconducting inactivated states. Both mechanisms slow the repriming of drug-modified channels under resting conditions and reduce the action potential firing rate. The charged forms of these drugs preferentially gain access to the binding site through the internal aqueous pathway created by the state-dependent opening of the channels. The uncharged and hydrophobic drugs display less state dependence and appear to access the binding site on closed and inactivated channels through fenestrations located in the walls of the cytoplasmic pore. Mutagenesis has identified several conserved residues that contribute to the cytoplasmic binding site for these drugs. Drug binding is modified by membrane voltage, interaction with permeant ions, and changes in extracellular pH.
Fig. 1 The organization of voltage-gated sodium channels.
Brevetoxins derivatives (PbTx-1 to PbTx-10) are potent lipid-soluble polyether neurotoxins produced by the marine dinoflagellate Karina brevis. Two skeletal types are known, and each type has a number of congeners that vary in the K-ring (type B) or J-ring (type A) sidechains. Ingestion of shellfish contaminated with K. brevis produces neurotoxic shellfish poisoning (NSP) in humans. NSP symptoms emanate from brevetoxin activation of neurotoxin site 5 on voltage-gated sodium channels (VGSC). Brevetoxin-3 (PbTx-3), a cytotoxin in antibody-drug conjugates (ADCs), is a lipophilic 11-ring polyether molecule that binds with high affinity to site 5 of the voltage-sensitive sodium (Na+) channel. Specific activities include: a shift of activation potential for Na+ channel opening to more negative values (i.e., channels open at standard resting potentials); inhibition of inactivation; increased mean channel open times; and induction of sub-conductance states. Together these effects result in a dose-dependent depolarization of excitable membranes.