Delivery of myo‐Inositol Hexakisphosphate to the Cell Nucleus with a Proline‐Based Cell‐Penetrating Peptide

Inositol hexakisphosphate (InsP6 ) is a central member of the inositol phosphate messengers in eukaryotic cells. Tools to manipulate the level of InsP6 , particularly with compartment selectivity, are needed to enable functional cellular studies. We present cationic octa-(4S)guanidiniumproline (Z8) for the delivery of InsP6 into the cell nucleus. CD spectroscopy, binding affinity, dynamic light scattering, and computational studies revealed that Z8 binds tightly to InsP6 and upon binding undergoes a conformational change from a PPII-helical structure to a structure that forms aggregates. The unique conformational features of the cationic oligoproline enable complex formation and cellular delivery of InsP6 with considerably greater efficacy than the flexible counterpart octaarginine.