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Protein therapy—delivery guaranteed

Nature Biotechnology volume 17, pages 1066–1067 (1999)Cite this article

In an eye-catching paper in Science, Steven Dowdy and colleagues have demonstrated the uptake of an injected protein in tissues throughout the living mouse1. Importantly, the protein, β-galactosidase (βGal, a large soluble enzyme) fused to a short cationic peptide from HIV-1 Tat, assumes activity within the target cells. These findings could have profound implications in medicine for diagnostics, drug delivery, and vaccination.

The use of ferry peptides and proteins to carry cargo into cells was reviewed recently2 in the wake of work on cells in culture demonstrating the efficient uptake of large proteins involved in cell signaling. That work built upon earlier studies, dating back as early as 1988, which used a variety of ferries derived from Tat, antennapedia protein, herpes simplex virus-1 VP22, Kaposi FGF signal sequence, and others. Given the success of uptake experiments in vitro, it is surprising that little has been published using intact animals. Barsoum and colleagues at Biogen did show in 1994 that βGal chemically crosslinked to a 35-residue Tat peptide was taken up by many tissues in the mouse, where the enzyme was active as judged by an in situ assay3. Importantly for the present discussion, no βGal activity was seen in brain sections. Although the Biogen group did not pursue the animal studies, they did carry out additional studies with cultured cells, including the use of fusion proteins rather than chemical conjugates4.

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Figure 1: Possible mechanism for uptake of the Tat–βGal fusion protein by cells.

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  1. professor in the department of medical biochemistry and genetics at the Texas A&M Health Science Center, College Station, 77843-1114, TX

    Hagan Bayley

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Bayley, H. Protein therapy—delivery guaranteed. Nat Biotechnol 17, 1066–1067 (1999). https://doi.org/10.1038/15050

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