Molecular Carriers May Fulfill Promise of Long-Sought 'Magic Bullet'

August 06, 1996

New Vehicle for Carrying Therapeutic Proteins into Living Cells
Contact: Misia Landau, landau@warren.med.harvard.edu
617-432-2342
Harvard Medical School

MOLECULAR CARRIERS MAY FULFILL PROMISE OF LONG-SOUGHT 'MAGIC BULLET'

BOSTON -- Harvard Medical School researchers have discovered a new vehicle for carrying therapeutic proteins into living cells. This latest response to the problem of delivering protein "drugs" to cancer cells or cells affected by inherited diseases is, quite literally, the short solution.

For several years, scientists have tried, with varying degrees of success, to harness the unique cell-penetrating ability of bacterial toxins and get them to drag along therapeutic proteins. Past attempts have teamed the desired protein with whole components of the bacterial toxin, sort of like using one ocean liner to steer another ocean liner through a narrow canal.

Now, the Harvard team has found that a tugboat-sized peptide, a building block of proteins, can replace one of the bulky components of the bacterial toxin and still deliver the goods. The team, led by John Collier, reports on the somewhat accidental finding in the August 6 issue of the Proceedings of the National Academy of Sciences.

In a commentary in the same issue, Anthony P. Pugsley of the Institut Pasteur notes that the Harvard discovery is "an important step toward application" of this much-touted "magic bullet" technology. He notes that the paired compounds are nontoxic and can be produced and purified through large-scale procedures currently used by industry.

Many bacterial toxins are composed of two protein subunits, one for toxicity and the other for binding; the former can't pack its punch unless the latter gets it into the cell. Some bacteria release the two components as separate proteins, the binding protein staking out the cell surface and the toxic protein later locating its partner and hooking up prior to invading the cell.

Scientists in the past have succeeded in linking a foreign protein to part of the toxic protein and getting it to drag the foreign protein to its partner at the cell surface and, in turn, getting the combination into the cell. Collier1s team found that certain small, ionically charged peptides can substitute for the toxin protein and succeed in dragging a foreign protein to the binder at the cell surface and getting the protein inside.

The finding came through a bit of serendipity while Collier's team was refining earlier work with the anthrax toxin. In some cell cultures, they had tagged the foreign protein with a short peptide used as a tool for protein purification. In those cultures, some of the foreign protein got into the cells when only the binding protein was present, not the toxic protein. In cultures in which the foreign protein was not tagged by the peptide, it could not get into the cells without the assistance of the carrier toxic protein.

In this series of experiments, the peptide was made of histidines. When the histidines were replaced by lysines, which carry a stronger positive charge, even more of the foreign protein made it into the cells. The results suggest that the peptides link up with either the bacterial binding protein on the surface of cells or another cell-surface component by means of electrostatic interactions.

Collier's team used diphtheria toxin as the foreign protein because they could measure cell penetration by looking for cell death caused by the diphtheria. The bacterial toxin in the experiment, anthrax, is not lethal at the concentrations or in the form the researchers used.

In his commentary, Pugsley suggested that in clinical application the foreign protein could be the dystrophin protein missing in the muscle cells of patients with muscular dystrophy, or any number of other proteins that could serve as therapy for cancer or other diseases.




Harvard Medical School

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