Boston Medical Center Corporation

Ryan Ratts

John R Murphy

The invention features methods for identifying compounds that inhibit cell death, and methods for identifying compounds that promote cell death, by blocking or accelerating, respectively, the translocation of the catalytic domain of toxins or transcription factors through the endosomal membrane into the cytosol of a cell. Also featured are methods for inhibiting cell death that include the administration of polypeptides that include a toxin consensus sequence recognized by one or more components of the cytosolic translocation factor complex.

Viral/bacterial toxin polypeptides and methods of using same

In vitro delivery of the diphtheria toxin (DT) catalytic (C) domain from the lumen of purified early endosomes to the external milieu requires the addition of both ATP and a cytosolic translocation factor (CTF) complex. The results presented here demonstrate that &#x3b2;-COP plays an essential role in the cytosolic release of the C-domain and is mediated by a consensus peptide sequence found on several bacterial toxins and in HIV-1 reverse transcriptase. The invention features methods for inhibiting cell death that include the administration of compounds based on this consensus sequence that inhibit the translocation of the catalytic domain of toxins or transcription factors. Also featured are methods for identifying compounds that inhibit cell death, and methods for identifying compounds that promote cell death by blocking or accelerating, respectively, the rate of toxin/factor endosomal translocation.

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Boston, MA, United States of America

Ryan Ratts