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

Abstract

Abstract Inositol hexakisphosphate (InsP 6 ) is a central member of the inositol phosphate messengers in eukaryotic cells. Tools to manipulate the level of InsP 6 , particularly with compartment selectivity, are needed to enable functional cellular studies. We present cationic octa‐(4S)guanidiniumproline ( Z8 ) for the delivery of InsP 6 into the cell nucleus. CD spectroscopy, binding affinity, dynamic light scattering, and computational studies revealed that Z8 binds tightly to InsP 6 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 InsP 6 with considerably greater efficacy than the flexible counterpart octaarginine.