Volume 10 Issue 8, August 2014

Comprehensive selectivity profiling is key for the development of safe drugs. Few current methods are capable of profiling large compound sets against entire target classes. The new EnPlex method expands the existing toolbox, allowing for the surveying of the serine hydrolase enzyme family.

Conventional allosteric modulators of G protein–coupled receptors (GPCRs) bind their target from the extracellular site. A new study shows that a GPCR's intracellular face can likewise be exploited. In particular, they sensitize a class B GPCR for activation by a hardly active peptide-hormone metabolite.

The gene cluster that produces the sponge-derived cytotoxin calyculin A has been located in an uncultivated bacterial symbiont. Biochemical analyses reveal a pyrophosphorylated protoxin as the true biosynthetic product and suggest that calyculins result from activated chemical defense.

There has been a strong effort to devise strategies to interfere with oncogenic Ras for cancer treatment. A review of recent advances in the development of small-molecule inhibitors that impair either Ras localization or protein interactions provides new optimism in this field.

Drug-resistance mutations provide a classical means to identify biological targets of small molecules. A combination of next-generation DNA sequencing with CRISPR-Cas9 genome editing confirms the targets of 6-thioguanine and triptolide and offers a general approach for target identification in cells.

Finding the biological targets of small molecules remains an important challenge in chemical biology and drug discovery. A method involving high-throughput sequencing, mutational analysis and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome editing identifies the targets and potential modes of compound resistance for two anticancer agents.

BETP, a positive allosteric modulator of GLP-1R, a class B GPCR and an important therapeutic target for type II diabetes, covalently modifies two cysteine residues at the receptor's cytoplasmic face, where one of these enhances agonist-induced signaling. [In the version of the Table of Contents initially published, the labels for the BETP conditions were swapped in graphical abstract of the Nolte et al. article. The error has been corrected in the HTML and PDF versions of the Table of Contents.]

The addition of a Notch signaling inhibitor to both mouse and human keratinocytes bypasses the use of oncogenes and p53 to increase transcription factor mediated–pluripotent stem cell reprogramming through blocking p21 expression.

Polybrominated aromatic natural products are pervasive in the marine food web. Genetic and biochemical data now establish their biosynthetic origins in marine bacteria, revealing a physiological brominase that uses an unusual decarboxylative mechanism.

Some toxic natural products are made in deactivated forms to avoid damage to the host. Metagenomic mining of sponge symbionts and biochemical characterization now define a new inactivating mechanism in which calyculin is made as a pyrophosphate by symbiotic bacteria and cleaved to the active monophosphate by the sponge.

The development of a new screening method called EnPlex allows rapid profiling of small molecules against an extensive selection of the serine hydrolase enzyme family, resulting in the identification of both off-targets and potential lead compounds.

C-terminal extended ubiquitin species, which have been associated with neurodegenerative disorders, were thought to inhibit proteasomes resulting in reduced protein clearance. Biochemical studies now provide evidence that these ubiquitin variants primarily block the activity of the deubiqutinating enzymes.

(+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile) is a plant hormone involved in plant development and stress response that signals through a COI1–JAZ co-receptor complex. Structure-guided design led to the identification of a coronatine derivative that antagonizes the COI1-JAZ interaction and blocks jasmonate signaling in plants.

Inclusions containing TDP43 are linked to pathologies in several neurodegenerative diseases such as ALS and FTD. Pathogenic TDP43 mutations are now found to shorten the protein's half-life in individual neurons. Stimulating autophagy with inhibitors improves TDP43 clearance and localization.

Spinach is an RNA aptamer analog of GFP that is widely used for fluorescent labeling of cellular RNAs. Crystal structures of Spinach–fluorophore complexes uncover an unusual G-quadruplex RNA fold that is involved in ligand recognition and tuning of Spinach fluorescence properties.