1.D.91. The pH-low Insertion Peptide (pHLIP) Family
The pH-low insertion peptide (pHLIP) is a leading peptide technology to target the extracellular acidosis that characterizes solid tumors. The pHLIP binds to lipid membranes and responds to acidification by undergoing a coupled folding/membrane insertion process. In the final transmembrane state, the C terminus of pHLIP becomes exposed to the cytoplasm of the target cell, providing a means to translocate membrane-impermeable drug cargoes across the plasma membrane of cancer cells. There exists a need to develop improved pHLIP variants to target tumors with greater efficiency. Characterization of such variants typically relies on determining the pK parameter, the pH midpoint of peptide insertion into the lipid bilayer. Scott et al. 2017 reported that the pK value is dependent on the method used for its determination. Membrane insertion of pHLIP involves at least four intermediate states, which are believed to be linked to the staggered titration of key acidic residues. Their data indicate that membrane translocation of the C terminus of pHLIP, the folding step more directly relevant to drug delivery, occurs primarily at acidic pH values.