Combinatorial targeting and discovery of ligand-receptors in organelles of mammalian cells

Roberto Rangel, Liliana Guzman-Rojas, Lucia G. le Roux, Fernanda I. Staquicini, Hitomi Hosoya, E. Magda Barbu, Michael G. Ozawa, Jing Nie, Kenneth Dunner, Robert R. Langley, E. Helene Sage, Erkki Koivunen, Juri G. Gelovani, Roy R. Lobb, Richard L. Sidman, Renata Pasqualini and Wadih Arap ()
Additional contact information
Roberto Rangel: David H. Koch Center, The University of Texas MD Anderson Cancer Center
Liliana Guzman-Rojas: David H. Koch Center, The University of Texas MD Anderson Cancer Center
Lucia G. le Roux: The University of Texas MD Anderson Cancer Center
Fernanda I. Staquicini: David H. Koch Center, The University of Texas MD Anderson Cancer Center
Hitomi Hosoya: David H. Koch Center, The University of Texas MD Anderson Cancer Center
E. Magda Barbu: David H. Koch Center, The University of Texas MD Anderson Cancer Center
Michael G. Ozawa: David H. Koch Center, The University of Texas MD Anderson Cancer Center
Jing Nie: David H. Koch Center, The University of Texas MD Anderson Cancer Center
Kenneth Dunner: The University of Texas MD Anderson Cancer Center
Robert R. Langley: The University of Texas MD Anderson Cancer Center
E. Helene Sage: The Benaroya Research Institute at Virginia Mason
Erkki Koivunen: David H. Koch Center, The University of Texas MD Anderson Cancer Center
Juri G. Gelovani: The University of Texas MD Anderson Cancer Center
Roy R. Lobb: Alvos Therapeutics
Richard L. Sidman: Beth Israel-Deaconess Medical Center
Renata Pasqualini: David H. Koch Center, The University of Texas MD Anderson Cancer Center
Wadih Arap: David H. Koch Center, The University of Texas MD Anderson Cancer Center

Nature Communications, 2012, vol. 3, issue 1, 1-10

Abstract: Abstract Phage display screening allows the study of functional protein–protein interactions at the cell surface, but investigating intracellular organelles remains a challenge. Here we introduce internalizing-phage libraries to identify clones that enter mammalian cells through a receptor-independent mechanism and target-specific organelles as a tool to select ligand peptides and identify their intracellular receptors. We demonstrate that penetratin, an antennapedia-derived peptide, can be displayed on the phage envelope and mediate receptor-independent uptake of internalizing phage into cells. We also show that an internalizing-phage construct displaying an established mitochondria-specific localization signal targets mitochondria, and that an internalizing-phage random peptide library selects for peptide motifs that localize to different intracellular compartments. As a proof-of-concept, we demonstrate that one such peptide, if chemically fused to penetratin, is internalized receptor-independently, localizes to mitochondria, and promotes cell death. This combinatorial platform technology has potential applications in cell biology and drug development.

Date: 2012
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DOI: 10.1038/ncomms1773

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