Abstract The human voltage-gated sodium channel hNa V 1.5 is essential for cardiac excitability. Though underrecognized, Na V 1.5 is also expressed in multiple cancers, promoting cell migration and malignancy. hNa V 1.5 is a therapeutic target but limited pharmacological isoform specificity presents a risk of side effects via neuronal and skeletal muscle Na V channels. Here we identify Mg 2+ -protoporphyrin IX (MgPpIX), a Mg-containing tetrapyrrole and intermediate in chlorophyll biosynthesis, as a potent inhibitor of hNa V 1.5 ( IC 50 of 1 nM). The activity profile of various metal protoporphyrins correlates with the electrostatic potential at the metal center of the compounds. MgPpIX is specific to hNa V 1.5, as no inhibition of other hNa V isoforms (hNa V 1.2, 1.4, 1.7, 1.8) was detected. A mutagenesis study and structural modeling reveals that MgPpIX stabilizes the domain-II voltage sensor in the deactivated conformation, with residues E795 and N803 being relevant determinants. MgPpIX also inhibits native Na V channels in breast cancer MDA-MB-231 and colorectal carcinoma SW-480 cell lines, and suppresses cell migration. MgPpIX is an exceptionally potent and specific inhibitor of hNa V 1.5 and may serve as a lead compound in anti-cancer drug development.
Jamili et al. (Thu,) studied this question.