Articles in 2010

In reviewing five years of progress in chemical biology, we consider the scientific and organizational challenges ahead for the field.

Drugs identified in high-content screens are often difficult to link to the cellular target, especially when multiple signaling pathways impinge on the phenotypic endpoint. A chemical-genetic approach in fruit fly cells now greatly improves the prioritization of drug hits by directing the screen toward a single pathway.

COX-2 is the enzyme largely responsible for causing inflammation, a common mechanism of disease. A study now reports that derivatives generated by COX-2 from naturally occurring ω-3 fatty acids are anti-inflammatory mediators.

These highlights showcase papers across the history and scope of Nature Chemical Biology.

Artificial biosynthetic pathways are typically assembled and optimized progressively, from earlier to later steps. This commentary highlights the potential of an alternate regressive method for biochemical pathway design and generation, inspired by the retro-evolution hypothesis and the concept of retrosynthesis. In addition to being a pathway design tool, 'bioretrosynthesis' has potential as a construction and optimization methodology.

Chemical screening in C. elegans is limited by the relatively poor target accessibility of small molecules. A systematic survey of drug-like small molecule accumulation and metabolism in C. elegans was used to create a computational tool for preselecting compounds likely to effectively perturb worms.

Semisynthetic versions of the small G protein Rab7 in the GDP-bound form have 1,000-fold higher affinity for regulators REP1 and RabGDI because of faster dissociation rates from Rab7-GTP, directly linking nucleotide exchange to Rab membrane targeting.

Crosslinks between the active and inactive M3R and the G-protein G_q to which it couples reveal GPCR-G protein movements that can occur upon agonist binding and define basic architectural features of the interface.

Intein splicing occurs in four steps, but the mechanisms controlling these steps — and thus preventing aberrant splicing — are unknown. Kinetic and NMR analysis of several complex constructs now identifies the rate limiting step as well as the conformational trigger that catalyzes this transformation.

Interaction between HIV-1 integrase and the cellular cofactor LEDGF/p75 is important for viral integration. Newly designed small molecules that block this interaction inhibit HIV replication, illustrating the potential of viral–host protein-protein interaction inhibitors.

The chemical synthesis of acylated dipeptide substrates for SfmC, a tetradomain NRPS enzyme, defines the mechanism of formation of two rings in saframycin and explains the unusual presence of a fatty acid loading system in this biosynthetic gene cluster.

Enhancing calnexin function by increasing the ER calcium concentration resculpts the mutant glucocerebrosidase folding free energy diagram in the ER of Gaucher's disease cells, enhancing folding at the expense of the ER-associated degradation pathway.

Synthetic biology enables the reprogramming of cells for useful applications. RNA selection approaches yielded an atrazine-binding riboswitch that was used to engineer Escherichia coli that migrate toward and catabolize this common herbicide.

Metabolomics analysis of stem cells and differentiated cells points to chemical unsaturation as a key feature of stem cell metabolites. Manipulation of these metabolites' concentrations directly influences stem cell behavior, highlighting biological oxidation as a driver for differentiation.

A new pathway screen for small molecules that suppress or enhance an RNAi phenotype in Drosophila cells was used to identify a collection of compounds that perturb different steps in the Rho pathway.

Six new species of electrophilic lipids identified in activated macrophages are derived from COX-2 action on ω-3 fatty acids and mediate anti-inflammatory and anti-oxidant activities.

Bacteria resistant to glycopeptides such as vancomycin sense the drugs and escape killing by remodeling synthesis of the cell wall target. A photoaffinity probe shows that induction of resistance relies on direct drug recognition by a glycopeptide sensor.

Functionally coupled motions between the voltage-sensing and the phosphatidylinositol phosphatase domains of the sea squirt protein Ci-VSP is mediated by PI(4,5)P₂ binding to the intervening linker, shedding light on the function of an unusual voltage-sensing protein.