Controversy still surrounds how certain cationic peptides enter the cell, spurred in part by this paper.1 The so-called cell-penetrating peptides (CPPs), which include short fragments of Tat from HIV-1, appeared to cross plasma membranes directly. This was surprising because the heavily arginated Tat is not the kind of molecule one often sees getting past hydrophobic membranes. Kamran Melikov, then a postdoc at the US National Institute of Child Health and Human Development, says he was also surprised that most studies had been done in fixed cells. "It looked counterintuitive to me to use a fixation protocol."
His lab, headed by Leonid Chernomordik, and a CNRS group at the University of Montpellier headed by Bernard Lebleu, showed that fixation and incomplete washing were responsible for the artifact with Tat and a nine-arginine fragment. Uptake was largely due to endocytosis, they suggested, which means any drug...
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