Bidirectional modulation of ion channels with divalent nanobodies

Abstract

Ion channels are essential for myriad cellular functions and their regulation is a critical pharmacological strategy for many diseases. However, traditional small-molecule and peptide-based therapeutics that target these channels are often inadequate, as their systemic distribution can lead to modulation of their target protein in off-target tissues. Gene therapy is an alluring alternative, with the potential to restrict transgene expression to a defined tissue. Here, we create a toolset to modulate the ubiquitin status of a target protein with divalent nanobodies (‘Divas’) that recruit the HECT domain of Nedd4L to a protein of interest.