D.j. Forster

Invited for the cover of this issue is the group of David Margulies at the Weizmann Institute of Science (Israel). The image highlights the analogy between fluorescent molecular sensors and a miniaturized camera that can capture changes that occur at the nanoscale and shed light on the structural state of proteins. Read the full text of the article at 10.1002/chem.201502069.

“We believe that the concept of combining a highly specific and a non-specific protein binder on a single molecular platform could open up new possibilities for detecting proteins and/or regulating their functions.” Read more about the story behind the cover in the Cover Profile and about the research itself on page 15981 ff. (DOI: 10.1002/chem.201502069).

Anticancer drug resistance demands innovative approaches that boost the activity of drugs against drug-resistant cancers without increasing the systemic toxicity. Here we show the use of enzyme-instructed self-assembly (EISA) to generate intracellular supramolecular assemblies that drastically boost the activity of cisplatin against drug-resistant ovarian cancer cells. We design and synthesize small peptide precursors as the substrates of carboxylesterase (CES). CES cleaves the ester bond pre-installed on the precursors to form the peptides that self-assemble in water to form nanofibers. At the optimal concentrations, the precursors themselves are innocuous to cells, but they double or triple the activity of cisplatin against the drug-resistant ovarian cancer cells. This work illustrates a simple, yet fundamental, new way to introduce non-cytotoxic components into combination therapies with cisplatin without increasing the systemic burden or side effects.

Cisplatin-boosting nanofibers: The design and synthesis is reported of small peptide precursors that can be cleaved by carboxylesterase (CES) to form peptides that self-assemble in water to form molecular nanofibers. The precursors themselves are innocuous to cells at optimal concentrations, but they double or triple the activity of cisplatin against drug-resistant ovarian cancer cells.

Engineered cytochrome P450 monooxygenase variants are reported as highly active and selective catalysts for the bioorthogonal uncaging of propargylic and benzylic ether protected substrates, including uncaging in living E. coli. observed selectivity is supported by induced-fit docking and molecular dynamics simulations. This proof-of-principle study points towards the utility of bioorthogonal enzyme/protecting group pairs for applications in the life sciences.

The great escape: Engineered cytochrome P450 monooxygenases were used for the removal of propargylic and benzylic ether protecting groups in vitro and in living E. coli. Deprotection resulted in the release of uncaged alcohols, which in this case display fluorescence properties. Such bioorthogonal enzyme/protecting group pairs could provide a means for the selective release of imaging agents or the catalytic activation of prodrugs at their site of action.