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A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging.

ABSTRACT: We describe the development of a bifunctional linker that simultaneously allows site-specific protein modification and palladium-mediated bioorthogonal decaging. This was enabled by a thioether binding motif in the propargyl carbamate linker and a readily available palladium complex. We demonstrate the efficiency of this reaction by controlled drug release from a PEGylated doxorubicin prodrug in cancer cells. The linker can be easily installed into cysteine bearing proteins which we demonstrated for the construction of an anti-HER2 nanobody-drug conjugate. Targeted delivery of the nanobody drug conjugate showed effective cell killing in HER2+ cells upon palladium-mediated decaging.

SUBMITTER: Stenton BJ

PROVIDER: S-EPMC5941270 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A thioether-directed palladium-cleavable linker for targeted bioorthogonal drug decaging.

Stenton Benjamin J BJ Oliveira Bruno L BL Matos Maria J MJ Sinatra Laura L Bernardes Gonçalo J L GJL

Chemical science 20180406 17

We describe the development of a bifunctional linker that simultaneously allows site-specific protein modification and palladium-mediated bioorthogonal decaging. This was enabled by a thioether binding motif in the propargyl carbamate linker and a readily available palladium complex. We demonstrate the efficiency of this reaction by controlled drug release from a PEGylated doxorubicin prodrug in cancer cells. The linker can be easily installed into cysteine bearing proteins which we demonstrated ...[more]

PMID: 29780549

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