Dimerization of alpha-Conotoxins as a Strategy to Enhance the Inhibition of the Human alpha 7 and alpha 9 alpha 10 Nicotinic Acetylcholine Receptors

The affinity of alpha-conotoxins, a class of nicotinic acetylcholine receptor (nAChR) peptide inhibitors, can be enhanced by dendrimerization. It has been hypothesized that this improvement arose from simultaneous binding of the alpha-conotoxins to several spatially adjacent sites. We here engineered several alpha-conotoxin dimers using a linker length compatible between neighboring binding sites on the same receptor. Remarkably, the dimer of alpha-conotoxin PeIA compared to the monomer displayed an increase in potency by 11-fold (IC50 = 1.9 nM) for the human alpha 9 alpha 10 nAChR. The dimerization of a-conotoxin RgIA# resulted in a dual inhibitor that targets both alpha 9 alpha 10 and alpha 7 nAChR subtypes with an IC50 = similar to 50 nM. The RgIA# dimer is therapeutically interesting because it is the first dual inhibitor that potently and selectively inhibits these two nAChR subtypes, which are both involved in the etiology of several cancers. We propose that the dimerization of alpha-conotoxins is a simpler and efficient alternative strategy to dendrimers for enhancing the activity of alpha-conotoxins.