Frontiers in chemical biology

Future perfect - p889

doi:10.1038/nchembio.1977

Abundant frontiers at the interface of chemistry and biology promise another decade of technological innovation and scientific discovery by chemical biologists.

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Frontiers in chemical biology

Targeting transcription is no longer a quixotic quest - pp891 - 894

Anna K Mapp, Rachel Pricer & Steven Sturlis

doi:10.1038/nchembio.1962

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.

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Frontiers in chemical biology

XFELs open a new era in structural chemical biology - pp895 - 899

Petra Fromme

doi:10.1038/nchembio.1968

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.

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Frontiers in chemical biology

Voices of chemical biology - pp900 - 901

doi:10.1038/nchembio.1975

We asked a collection of chemical biologists: "What is the most exciting frontier area in chemical biology, and what key technology is needed to advance knowledge and applications at this frontier?"

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Frontiers in chemical biology

Discovery and characterization of smORF-encoded bioactive polypeptides - pp909 - 916

Alan Saghatelian & Juan Pablo Couso

doi:10.1038/nchembio.1964

Analysis of genomes, transcriptomes and proteomes reveals the existence of hundreds to thousands of translated, yet non-annotated, short open reading frames (small ORFs or smORFs). The discovery of smORFs and their protein products, smORF-encoded polypeptides (SEPs), points to a fundamental gap in our knowledge of protein-coding genes. Various studies have identified central roles for smORFs in metabolism, apoptosis and development. The discovery of these bioactive SEPs emphasizes the functional potential of this unexplored class of biomolecules. Here, we provide an overview of this emerging field and highlight the opportunities for chemical biology to answer fundamental questions about these novel genes. Such studies will provide new insights into the protein-coding potential of genomes and identify functional genes with roles in biology and disease.

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Frontiers in chemical biology

Imaging and manipulating proteins in live cells through covalent labeling - pp917 - 923

Lin Xue, Iuliia A Karpenko, Julien Hiblot & Kai Johnsson

doi:10.1038/nchembio.1959

The past 20 years have witnessed the advent of numerous technologies to specifically and covalently label proteins in cellulo and in vivo with synthetic probes. These technologies range from self-labeling proteins tags to non-natural amino acids, and the question is no longer how we can specifically label a given protein but rather with what additional functionality we wish to equip it. In addition, progress in fields such as super-resolution microscopy and genome editing have either provided additional motivation to label proteins with advanced synthetic probes or removed some of the difficulties of conducting such experiments. By focusing on two particular applications, live-cell imaging and the generation of reversible protein switches, we outline the opportunities and challenges of the field and how the synergy between synthetic chemistry and protein engineering will make it possible to conduct experiments that are not feasible with conventional approaches.

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Frontiers in chemical biology

Chemical modulators of ribosome biogenesis as biological probes - pp924 - 932

Jonathan M Stokes & Eric D Brown

doi:10.1038/nchembio.1957

Small-molecule inhibitors of protein biosynthesis have been instrumental in the dissection of the complexities of ribosome structure and function. Ribosome biogenesis, on the other hand, is a complex and largely enigmatic process for which there is a paucity of chemical probes. Indeed, ribosome biogenesis has been studied almost exclusively using genetic and biochemical approaches without the benefit of small-molecule inhibitors of this process. Here, we provide a perspective on the promise of chemical inhibitors of ribosome assembly for future research. We explore key obstacles that complicate the interpretation of studies aimed at perturbing ribosome biogenesis in vivo using genetic methods, and we argue that chemical inhibitors are especially powerful because they can be used to induce perturbations in a manner that obviates these difficulties. Thus, in combination with leading-edge biochemical and structural methods, chemical probes offer unique advantages toward elucidating the molecular events that define the assembly of ribosomes.

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Frontiers in chemical biology

Progress and challenges for chemical probing of RNA structure inside living cells - pp933 - 941

Miles Kubota, Catherine Tran & Robert C Spitale

doi:10.1038/nchembio.1958

Proper gene expression is essential for the survival of every cell. Once thought to be a passive transporter of genetic information, RNA has recently emerged as a key player in nearly every pathway in the cell. A full description of its structure is critical to understanding RNA function. Decades of research have focused on utilizing chemical tools to interrogate the structures of RNAs, with recent focus shifting to performing experiments inside living cells. This Review will detail the design and utility of chemical reagents used in RNA structure probing. We also outline how these reagents have been used to gain a deeper understanding of RNA structure in vivo. We review the recent merger of chemical probing with deep sequencing. Finally, we outline some of the hurdles that remain in fully characterizing the structure of RNA inside living cells, and how chemical biology can uniquely tackle such challenges.

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Frontiers in chemical biology

Functional genomics to uncover drug mechanism of action - pp942 - 948

Sebastian M B Nijman

doi:10.1038/nchembio.1963

The upswing in US Food and Drug Administration and European Medicines Agency drug approvals in 2014 may have marked an end to the dry spell that has troubled the pharmaceutical industry over the past decade. Regardless, the attrition rate of drugs in late clinical phases remains high, and a lack of target validation has been highlighted as an explanation. This has led to a resurgence in appreciation of phenotypic drug screens, as these may be more likely to yield compounds with relevant modes of action. However, cell-based screening approaches do not directly reveal cellular targets, and hence target deconvolution and a detailed understanding of drug action are needed for efficient lead optimization and biomarker development. Here, recently developed functional genomics technologies that address this need are reviewed. The approaches pioneered in model organisms, particularly in yeast, and more recently adapted to mammalian systems are discussed. Finally, areas of particular interest and directions for future tool development are highlighted.

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