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Mechanism for Escaping Cellular Trojan Horse Detailed

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Molecular troops can sneak past the cell’s ramparts if they are tucked inside an endosome, but they can become trapped, unable to escape the endosome and roam the cytosol. The endosome, then, can be a tricky sort of Trojan horse. It needs the equivalent of better escape panels.

Intent on designing a better Trojan horse, a latter-day Odysseus, Jean-Philippe Pellois, Ph.D., is leading an effort at Texas  A&M University to overcome endosomal entrapment, a severe limitation in the delivery of biologics into cells. Dr. Pellois and colleagues recently extended their previous work, which has already identified a cell-penetrating peptide, the reagent dfTAT, a disulfide bond dimer of the peptide transactivator of transcription (TAT) labeled with the fluorophore tetramethylrhodamine. dfTAT acts like a key that can open an endosomal trapdoor.

Although Dr. Pellois’ team had determined that dfTAT can circumvent the problem of endosomal entrapment by mediating endosomal leakage efficiently and without toxicity, dfTAT’s mechanism of action remained unknown. So, Dr. Pellois’ team took a closer look at dfTAT’s progress though the endocytic pathway.

The results of this work appeared May 5 in the journal Cell Chemical Biology, in an article entitled, “The Late Endosome and Its Lipid BMP Act as Gateways for Efficient Cytosolic Access of the Delivery Agent dfTAT and Its Macromolecular Cargos.” The article essentially describes the lock that dfTAT is able to open.

“By modulating the trafficking of the [cell-penetrating] peptide within the endocytic pathway, we identify late endosomes as the organelles rendered leaky by dfTAT,” wrote the article’s authors. “We establish that dfTAT binds bis(monoacylglycero)phosphate (BMP), a lipid found in late endosomes, and that the peptide causes the fusion and leakage of bilayers containing BMP.”

This work promises to inform future efforts to create better endosomal escape modalities. Such efforts may lead to multiple keys to multiple locks, or at least more smoothly operating lock-and-key combinations.

“In the Trojan horse example, if you are able to get the horse through the city gate, but what’s inside the horse is stuck, it’s useless,” said Dr. Pellois. “We knew we had found a key to the Trojan horse trapdoor, but we didn’t know what the key was turning, so to speak, to get into the cell without harming the membrane. In our most recent work, we looked at where the key was going and what it was doing, and we found the lock.”

The results of his team’s current work, adds Dr. Pellois, may make it easier to design new sets of keys and develop more effective cell biology, biotechnology, and therapeutic applications. “We can send probes into the cell and spy on the cells to see what the cell is doing inside,” he explained. “And the lock we found is common across all cell lines. And whereas cell biologists might think that opening the trapdoor would be toxic to the cell, that has not been so.”

He noted this finding is potentially useful to the pharmaceutical industry in designing medicines for better delivery to the source of the disease inside cells.

“In a metabolic disease, an enzyme is mutated or deficient in the cell,” Dr. Pellois continued. “So it would be helpful to be able to replace the defective enzyme with one that is working properly, for example.”

He indicated that the technique may eventually be applicable for a host of diseases such as HIV/AIDS and cancer and for regenerative medicine for treating heart and liver cells.

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