Articles in 2010

Increased transparency and consistency in reporting well-validated chemical probes will further enhance the impact of this exciting and rapidly advancing area of chemical biology.

Chemical biologists frequently aim to create small-molecule probes that interact with a specific protein in vitro in order to explore the role of the protein in a broader biological context (cells or organisms), but a common understanding of what makes a high-quality probe is lacking. Here I propose a set of principles to guide probe qualification.

The complexity of cancer signaling and the resulting difficulties in target selection have strongly biased kinase drug discovery towards clinically validated targets. Recently, novel kinase targets that are uncharacterized have emerged from genome sequencing and RNAi studies. Chemical probes are urgently needed to functionally annotate these kinases and to stimulate new drug discovery efforts.

Bioactive compounds are most frequently identified via high-throughput screening campaigns. This article discusses the strengths and weaknesses of the most popular screening approaches and the utility of compounds derived from them.

Beewolf digger wasps protect their larvae from microbial infestation by cultivating Streptomyces bacteria that produce antimicrobial compounds. A new study uses intact specimens to investigate the placement and production of nine antibiotics that combine to kill a wide range of pathogens.

Bacterial cultures can express proteins in high yields but cannot create mammalian N-glycoforms. Engineering of the glycosylation machinery of C. jejuni and its transfer into E. coli, combined with trimming and rebuilding of the N-linked glycan, now provides a robust route to glycoproteins.

Profiling of a combinatorial library of post-translationally modified histone H3–based peptides reveals that Thr3 phosphorylation, Arg2 methylation and Thr6 phosphorylation can modulate recognition of Lys4 methylation status by PHD fingers. Additionally, Thr6 phosphorylation, a previously undescribed modification, is shown to exist in native histones.

Determining relevant targets of promiscuous kinase inhibitors has proven difficult. A combination of two mass spectrometry–based proteomic approaches, RNAi depletion and rescue studies with drug-resistant mutants now reveal that SRC, FYN and EGFR are functionally important targets of dasatinib in lung cancer cells.

A caged version of the neurotransmitter GABA can be activated by two-photon excitation to evoke small, fast GABAergic currents to allow functional mapping of GABA receptor distribution in living brain tissue with single-synapse resolution.

Ribosomal decoding is dependent on wobble base pairing, which frequently involves modified nucleotides in the tRNA anticodon loop. The discovery of a new guanidine-modified base, 2-agmatinylcytidine, in the tRNA^Ile of archaea uncovers the mechanism for AUA decoding in these organisms.

In contrast to perceived nonselectivity, biochemical profiling reveals that currently available HDAC inhibitors predominantly inhibit only class I and IIb HDAC enzymes. A new pan-selective inhibitor, obtained by screening a focused library, provides an important tool for studying class IIa HDACs.

Reprogramming cell fates might cure or ameliorate many diseases. New results show that chemical reprogramming can be used in living animals to restore missing cell types.

A process in which peptide nucleic acids may be used for in vitro evolution has been developed. This method can offer enormous opportunities to evolve stable, non-natural molecules for therapeutic applications.

Antibiotics can break down through the action of enzymes or through non-enzymatic processes. In the case of tetracycline, this drug 'debris' can have unexpected biological activities, including selection against resistance.

Scientists need to devote more attention to the citation lists of scientific papers—the connectivity and usefulness of the scientific literature depend upon it.

Phosphoinositide 3-OH kinases (PI(3)Ks) are important lipid signaling enzymes and exciting drug targets for a number of human diseases. The first, much anticipated crystal structure of the delta isoform of PI(3)K provides surprising new insights into the selectivity of inhibitors for this versus other PI(3)K isoforms and facilitates the design of improved drugs.