Spatio‐Temporal Photoactivation of Cytotoxic Proteins

Protein therapeutics offer exquisite selectivity in targeting cellular processes and behaviors, but are rarely used against non‐cell surface targets due to their poor cellular uptake. While cell‐penetrating peptides can be used to deliver recombinant proteins to the cytosol, it is generally difficul...

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Published inChembiochem : a European journal of chemical biology Vol. 23; no. 12; pp. e202200115 - n/a
Main Authors Cruz‐Samperio, Raquel, Mart, Robert J., Luk, Louis Y. P., Tsai, Yu‐Hsuan, Jones, Arwyn T., Allemann, Rudolf K.
Format Journal Article
LanguageEnglish
Published Weinheim Wiley Subscription Services, Inc 20.06.2022
John Wiley and Sons Inc
Subjects
barnase
Cell surface
Cytosol
Cytotoxicity
inteins
Irradiation
light-activation
Peptides
Photoactivation
photocaging
Proteins
Radiation
saporin
Selectivity
Splicing
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Summary:Protein therapeutics offer exquisite selectivity in targeting cellular processes and behaviors, but are rarely used against non‐cell surface targets due to their poor cellular uptake. While cell‐penetrating peptides can be used to deliver recombinant proteins to the cytosol, it is generally difficult to selectively deliver active proteins to target cells. Here, we report a recombinantly produced, intracellular protein delivery and targeting platform that uses a photocaged intein to regulate the spatio‐temporal activation of protein activity in selected cells upon irradiation with light. The platform was successfully demonstrated for two cytotoxic proteins to selectively kill cancer cells after photoactivation of intein splicing. This platform can generically be applied to any protein whose activity can be disrupted by a fused intein, allowing it to underpin a wide variety of future protein therapeutics. Successful photoactivation of proteins in mammalian cells is reported. We use a photocaged‐intein (shown in yellow and pink respectively) to deactivate the protein of interest (shown in grey) and we deliver this construct to mammalian cells to activate it in vivo using light (active protein shown in red and light in blue). In this work we achieved photocontrol of strong cytotoxic proteins in cancer cells, describing a possible new generation of protein therapeutics.
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ISSN:1439-4227
1439-7633
1439-7633
DOI:10.1002/cbic.202200115