Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity.

Although bespoke, sequence-specific proteases have the potential to advance biotechnology and medicine, generation of proteases with tailor-made cleavage specificities remains a major challenge. We developed a phage-assisted protease evolution system with simultaneous positive and negative selection and applied it to three botulinum neurotoxin (BoNT) light-chain proteases. We evolved BoNT/X protease into separate variants that preferentially cleave vesicle-associated membrane protein 4 (VAMP4) and Ykt6, evolved BoNT/F protease to selectively cleave the non-native substrate VAMP7, and evolved BoNT/E protease to cleave phosphatase and tensin homolog (PTEN) but not any natural BoNT protease substrate in neurons.

Synthesis and Biological Evaluation of a Depsipeptidic Histone Deacetylase Inhibitor via a Generalizable Approach Using an Optimized Latent Thioester Solid-Phase Linker.

We describe the synthesis of Xyzidepsin, a depsipeptidic analogue of HDAC inhibitor Romidepsin (FK228), using a solid-phase strategy. Our latent thioester solid-phase linker was synthesized in 92% yield (three steps). Chemoselective conditions unmasked the thioester functionality and cyclized the depsipeptidic macrocycle.

Enantioselective photochemistry through Lewis acid-catalyzed triplet energy transfer.

Relatively few catalytic systems are able to control the stereochemistry of electronically excited organic intermediates. Here we report the discovery that a chiral Lewis acid complex can catalyze triplet energy transfer from an electronically excited photosensitizer. We applied this strategy to asymmetric [2 + 2] photocycloadditions of 2'-hydroxychalcones, using tris(bipyridyl) ruthenium(II) as a sensitizer.

Dual Catalysis Strategies in Photochemical Synthesis.

The interaction between an electronically excited photocatalyst and an organic molecule can result in the genertion of a diverse array of reactive intermediates that can be manipulated in a variety of ways to result in synthetically useful bond constructions. This Review summarizes dual-catalyst strategies that have been applied to synthetic photochemistry. Mechanistically distinct modes of photocatalysis are discussed, including photoinduced electron transfer, hydrogen atom transfer, and energy transfer.

Photocatalytic synthesis of dihydrobenzofurans by oxidative [3+2] cycloaddition of phenols.

We report a protocol for oxidative [3+2] cycloadditions of phenols and alkenes applicable to the modular synthesis of a large family of dihydrobenzofuran natural products. Visible-light-activated transition metal photocatalysis enables the use of ammonium persulfate as an easily handled, benign terminal oxidant. The broad range of organic substrates that are readily oxidized by photoredox catalysis suggests that this strategy may be applicable to a variety of useful oxidative transformations.