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

Abstract

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.