Exploring the chemical-functional space of cell-penetrating peptides

Abstract

Cell penetrating peptides (CPPs) are an increasingly growing part of fundamental and applied peptide research. Using their capacity to cross cell barriers, they have already been successfully applied as carriers for problematic cargos like DNA, (si)RNA, proteins and other peptides, (poly/oligo) saccharides and small molecules. Several hundreds of CPPs, showing different properties and activities, are already reported in the literature. To clarify the different types of actions in cell-penetrating behaviour, a database of more than 200 peptides was build, covering the CPPs described over the last five years and for which quantitative data were available. Seen the wide range of techniques, cell lines, peptide concentrations and other operational parameters used to quantify the cellular uptake, a unified response for cellular uptake was firstly defined based upon a concentration corrected standardized response relative to the concentration corrected response of Penetratin, a well known and characterized CPP. In this way a “meta-analytical” comparison of the cellular uptake of different CPPs is established, which was currently hardly needed. Therefore a chemical space was developed using more than 3000 descriptors, calculated from the optimized 3D-structure of the CPPs. By combining these descriptors and the unified responses, clusters of peptides are obtained from which model CPPs can be rationally selected and QSPRs and mechanisms of action established