Making the Membrane Disappear with Spontaneous Membrane Translocating Peptides

Abstract

The hydrocarbon core of a lipid bilayer membrane is the most hydrophobic microenvironment found in nature. As a result, the membrane is a strict barrier to the direct passage of polar or charged solutes. This property is critical for the biological function of membranes. Yet, the ability to bypass this barrier with polar compounds on demand would be very useful in cell biology, and is currently one of the biggest challenges for drug design and delivery. While the translocation of lipophilic small molecules across membranes is well described, basic knowledge is lacking to explain how some polar peptides can bypass the membrane barrier. Among these Spontaneous Membrane Translocating Peptides (SMTPs) are a family of water-soluble, cationic translocating peptides that we have discovered. These fundamentally unique peptides may hold the key to understanding how bioactive molecules can be delivered directly to cells. Despite the fact that they have several arginine residues, and are predicted not to be membrane permeable based on their polarity, they cross synthetic bilayers and cell membranes rapidly without any disruption or permeabilization. They also cross cellular membranes without relying on endocytosis (unlike the well-studied cell penetrating peptides), and deliver polar, membrane impermeant cargoes directly to cells. Here we describe the activity of these peptides using both synthetic bilayer systems and living cells.