Epidithiodiketopiperazines: Strain-Promoted Thiol-Mediated Cellular Uptake at the Highest Tension | Zendy

Lili Zong | Zendy; Eline Bartolami | Zendy; Daniel Abegg | Zendy; Alexander Adibekian | Zendy; Naomi Sakai | Zendy; Stefan Matile | Zendy

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Epidithiodiketopiperazines: Strain-Promoted Thiol-Mediated Cellular Uptake at the Highest Tension

Author(s) -

Lili Zong,

Eline Bartolami,

Daniel Abegg,

Alexander Adibekian,

Naomi Sakai,

Stefan Matile

Publication year - 2017

Publication title -

acs central science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 4.893

H-Index - 76

eISSN - 2374-7951

pISSN - 2374-7943

DOI - 10.1021/acscentsci.7b00080

Subject(s) - thiol , cytosol , chemistry , endocytosis , endosome , biophysics , transferrin receptor , receptor mediated endocytosis , biochemistry , transferrin , receptor , biology , enzyme

The disulfide dihedral angle in epidithiodiketopiperazines (ETPs) is near 0°. Application of this highest possible ring tension to strain-promoted thiol-mediated uptake results in efficient delivery to the cytosol and nucleus. Compared to the previous best asparagusic acid (AspA), ring-opening disulfide exchange with ETPs occurs more efficiently even with nonactivated thiols, and the resulting thiols exchange rapidly with nonactivated disulfides. ETP-mediated cellular uptake is more than 20 times more efficient compared to AspA, occurs without endosomal capture, depends on temperature, and is "unstoppable" by inhibitors of endocytosis and conventional thiol-mediated uptake, including siRNA against the transferrin receptor. These results suggest that ETP-mediated uptake not only maximizes delivery to the cytosol and nucleus but also opens the door to a new multitarget hopping mode of action.

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