Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.

WRN helicase is a promising target for treatment of cancers with microsatellite instability (MSI) due to its essential role in resolving deleterious non-canonical DNA structures that accumulate in cells with faulty mismatch repair mechanisms. Currently there are no approved drugs directly targeting human DNA or RNA helicases, in part owing to the challenging nature of developing potent and selective compounds to this class of proteins. Here we describe the chemoproteomics-enabled discovery of a clinical-stage, covalent allosteric inhibitor of WRN, VVD-133214.

Total Synthesis of (+)-Euphorikanin A via an Atropospecific Cascade.

A total synthesis of the ingenane-derived diterpenoid (+)-euphorikanin A is described. Key to the strategy is a stereocontrolled one-pot sequence consisting of transannular aldol addition reaction, hemiketal formation, and subsequent semipinacol rearrangement that efficiently leads to the complete euphorikanin skeleton. Atroposelective ring-closing olefin metathesis proved critical for the stereospecific cascade, leading to formation of a ()-bicyclo[7.

Enantioselective Total Synthesis of (+)-Euphorikanin A.

We disclose the first total synthesis of (+)-euphorikanin A, an ingenane-derived natural product featuring an unprecedented 5/6/7/3-fused tetracyclic skeleton. Key to the approach is a SmI-mediated ketyl-enoate reaction that leads to the formation of two rings in a single step. The polarity-reversed cyclization proceeds in excellent yield and high diastereoselectivity.

The N-terminal peptide of the transglutaminase-activating metalloprotease inhibitor from Streptomyces mobaraensis accommodates both inhibition and glutamine cross-linking sites.

Streptomyces mobaraensis is a key player for the industrial production of the protein cross-linking enzyme microbial transglutaminase (MTG). Extra-cellular activation of MTG by the transglutaminase-activating metalloprotease (TAMP) is regulated by the TAMP inhibitory protein SSTI that belongs to the large Streptomyces subtilisin inhibitor (SSI) family. Despite decades of SSI research, the binding site for metalloproteases such as TAMP remained elusive in most of the SSI proteins.

Features of the transglutaminase-activating metalloprotease from Streptomyces mobaraensis DSM 40847 produced in Escherichia coli.

Transglutaminase from Streptomyces mobaraensis (MTG) is an important enzyme for numerous industrial applications. Recombinant production requires proteolytic activation of the zymogen. The study provides a convenient procedure for the preparation of the transglutaminase-activating metalloprotease (TAMP) in Escherichia coli.

Synthesis of Alfaprostol and PGF through 1,4-Addition of an Alkyne to an Enal Intermediate as the Key Step.

The veterinary drug Alfaprostol and prostaglandin PGF have been synthesized in just nine steps. The strategy involved the conjugate addition of an alkyne to a bicyclic enal, available in three steps by a proline-catalyzed aldol reaction of succinaldehyde. In the case of Alfaprostol, this resulted in the shortest synthesis reported to date.