• Intracellular Target-Specific Accretion of Cell Penetrating Peptides and Bioportides: Ultrastructural and Biological Correlates

      Jones, Sarah; Uusna, Julia; Langel, Ülo; Howl, John; Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1LY, United Kingdom; Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia; Institute of Technology, University of Tartu, Nooruse 1, 50411, Tartu, Estonia; Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wulfruna Street, Wolverhampton, WV1 1LY, United Kingdom (American Chemical Society, 2015-12-14)
      Cell penetrating peptide (CPP) technologies provide a viable strategy to regulate the activities of intracellular proteins that may be intractable to other biological agents. In particular, the cationic helical domains of proteins have proven to be a reliable source of proteomimetic bioportides, CPPs that modulate the activities of intracellular proteins. In this study we have employed live cell imaging confocal microscopy to determine the precise intracellular distribution of a chemically diverse set of CPPs and bioportides. Our findings indicate that, following efficient cellular entry, peptides are usually accreted at intracellular sites rather than being freely maintained in an aqueous cytosolic environment. The binding of CPPs to proteins in a relatively stable manner provides a molecular explanation for our findings. By extension, it is probable that many bioportides influence biological processes through a dominant-negative influence upon discrete protein–protein interactions. As an example, we report that bioportides derived from the leucine-rich repeat kinase 2 discretely influence the biology and stability of this key therapeutic target in Parkinson’s disease. The intracellular site-specific accretion of CPPs and bioportides can also be readily modulated by the attachment of larger cargoes or, more conveniently, short homing motifs. We conclude that site-specific intracellular targeting could be further exploited to expand the scope of CPP technologies.