News & Comment

Misregulated transcription factors play prominent roles in human disease, but their dynamic protein-protein interaction network has long made the goal of transcription-targeted therapeutics impractical. Recent advances in technologies for modulating protein interaction networks mean that the end of the quest is in sight.

X-ray crystallography, the workhorse of structural biology, has been revolutionized by the advent of serial femtosecond crystallography using X-ray free electron lasers. Here, the fast pace and history of discoveries are discussed together with current challenges and the method's great potential to make new structural discoveries, such as the ability to generate molecular movies of biomolecules at work.

A 'chemical biology of cellular membranes' must capture the way that mesoscale perturbations tune the biochemical properties of constituent lipid and protein molecules and vice versa. Whereas the classical paradigm focuses on chemical composition, dynamic modulation of the physical shape or curvature of a membrane is emerging as a complementary and synergistic modus operandi for regulating cellular membrane biology.

Protein kinases have emerged as one of the most successful families of drug targets. To date, most selective kinase inhibitors have been discovered serendipitously either through broad selectivity screening or through the discovery of unique binding modes. Here we discuss design strategies that could lead to a broader coverage of the kinome with selective inhibitors and to a more rational approach for developing them.

Chemical compounds designed to enhance understanding of host-pathogen interaction together with next-generation 'smart drugs' will rationally drive the discovery of promising new host-directed targets against pathogens including Mycobacterium tuberculosis, the causative agent of tuberculosis.

The recent emergence of signaling roles for transition metals presages a broader contribution of these elements beyond their traditional functions as metabolic cofactors. New chemical approaches to identify the sources, targets and physiologies of transition-metal signaling can help expand understanding of the periodic table in a biological context.

As the identification of previously undetected microbial biosynthetic pathways burgeons, there arises the question of how much new chemistry is yet to be found. This, in turn, devolves to: what kinds of biosynthetic enzymatic transformations are yet to be characterized?

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

Epigenetic chemical probes are having a strong impact in biological discovery and target validation. Systematic coverage of emerging epigenetic target classes with these potent, selective, cell-active chemical tools will profoundly influence understanding of the human biology and pathology of chromatin-templated mechanisms.

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

Recent studies suggest that iron-sulfur (Fe-S) proteins may be unexpectedly abundant and functionally diverse in mammalian cells, but their identification still remains difficult. The use of informatics along with traditional spectroscopic analyses could be key to discovering new Fe-S proteins and validating their functional roles.

Enzymology has been a vital link between chemistry and biology in the second half of the twentieth century. A range of emerging scientific challenges is presenting the field with exciting opportunities to continue thriving in the future.

The pharmaceutical industry continues to experience significant attrition of drug candidates during phase 2 proof-of-concept clinical studies. We describe some questions about the characteristics of protein targets and small-molecule drugs that may be important to consider in drug-discovery projects and could improve prospects for future clinical success.

Protein aggregation is a central hallmark of many neurodegenerative disorders, but the relationship of aggregate structural diversity to the resultant cellular cytotoxicity and phenotypic diversity has remained obscure. Recent advances in understanding the mechanisms of protein aggregation and their physiological consequences have been achieved through chemical biology approaches, such as rationally designed protein modifications and chemical probes, providing crucial mechanistic insights and promise for therapeutic strategies for brain disorders.