Membrane active, pH-sensitive peptides are needed in biotechnology and medicine. By rationally designing a peptide library, and using a high-throughput functional screen, we have discovered a family of peptides that cause macromolecular poration in synthetic membranes at low concentration, in a way that is triggered by acidic pH. These peptides, which we named the pH-dependent Delivery (pHD) peptides, are unprecedented in their ability to cause highly efficient, pH-triggered leakage of large molecules through synthetic membranes. At pH 7 or above, the members of this synthetically evolved family of sequences are essentially inactive; they induce little release of small or large molecules from lipid bilayer vesicles. Yet, at pH ≤ 6, they bind to membranes, fold into a-helices, and enable efficient release of macromolecules at very low peptide concentration.  Subsequent biophysical characterization has revealed that the activity of these peptides is extremely sensitive to the composition of the lipid bilayer. Currently we are working to understand the principles of peptide-lipid interactions that underlie the observed exquisite sensitivity.

The peptides we have selected cause pH-triggered macromolecular poration, a property that could potentially be exploited in multiple ways. There are applications in medicine where acidic environmental pH can trigger the activity of the new peptides. One example is the acidic environment around solid tumors where tumor selective cytolytic activity could be triggered. A second example are acidified organelles, such as endosomes and lysosomes, where selective cargo delivery into the cytosol could be enabled by pH-induced macromolecular poration. We are exploring the utility of the pHD peptides for such applications.