With the June 2015 issue, Nature Chemical Biology celebrates 10 years of serving the chemical biology community. In honor of this anniversary, we are presenting a collection of articles that highlights the scientific accomplishments and promising future of chemical biology.
doi:10.1038/nchembio.1832
Chemical biology may elude simple definitions, but there remains no question that chemical biologists have crafted a compelling interdisciplinary narrative that advances science and benefits society.
Full Text - What's in a name? | PDF (101 KB) - What's in a name?
doi:10.1038/nchembio.1882
Chemical probes are proven tools for biological research and early-stage drug development, but how can chemical biologists make them more useful to the broader scientific community?
Full Text - Probing questions | PDF (102 KB) - Probing questions
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.
doi:10.1038/nchembio.1815
We present a selection of papers published in Nature Chemical Biology over the past decade that reflect the diversity and excitement of chemical biology research.
Mark E Bunnage, Adam M Gilbert, Lyn H Jones & Erik C Hett
doi:10.1038/nchembio.1813
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.
Full Text - Know your target, know your molecule | PDF (584 KB) - Know your target, know your molecule
Motomasa Tanaka & Yusuke Komi
doi:10.1038/nchembio.1818
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.
Full Text - Layers of structure and function in protein aggregation | PDF (581 KB) - Layers of structure and function in protein aggregation
Chaitan Khosla
doi:10.1038/nchembio.1844
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.
Full Text - Quo vadis, enzymology? | PDF (2,046 KB) - Quo vadis, enzymology?
Tracey A Rouault
doi:10.1038/nchembio.1843
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.
Full Text - Iron-sulfur proteins hiding in plain sight | PDF (969 KB) - Iron-sulfur proteins hiding in plain sight
Cheryl H Arrowsmith, James E Audia, Christopher Austin, Jonathan Baell, Jonathan Bennett, Julian Blagg, Chas Bountra, Paul E Brennan, Peter J Brown, Mark E Bunnage, Carolyn Buser-Doepner, Robert M Campbell, Adrian J Carter, Philip Cohen, Robert A Copeland, Ben Cravatt, Jayme L Dahlin, Dashyant Dhanak, Aled M Edwards, Mathias Frederiksen, Stephen V Frye, Nathanael Gray, Charles E Grimshaw, David Hepworth, Trevor Howe, Kilian V M Huber, Jian Jin, Stefan Knapp, Joanne D Kotz, Ryan G Kruger, Derek Lowe, Mary M Mader, Brian Marsden, Anke Mueller-Fahrnow, Susanne Müller, Ronan C O'Hagan, John P Overington, Dafydd R Owen, Saul H Rosenberg, Brian Roth, Ruth Ross, Matthieu Schapira, Stuart L Schreiber, Brian Shoichet, Michael Sundström, Giulio Superti-Furga, Jack Taunton, Leticia Toledo-Sherman, Chris Walpole, Michael A Walters, Timothy M Willson, Paul Workman, Robert N Young & William J Zuercher
doi:10.1038/nchembio.1867
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.
Full Text - The promise and peril of chemical probes | PDF (736 KB) - The promise and peril of chemical probes
Andrea Huston, Cheryl H Arrowsmith, Stefan Knapp & Matthieu Schapira
doi:10.1038/nchembio.1871
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.
Full Text - Probing the epigenome | PDF (1,284 KB) - Probing the epigenome
Christopher J Chang
doi:10.1038/nchembio.1913
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.
Full Text - Searching for harmony in transition-metal signaling | PDF (457 KB) - Searching for harmony in transition-metal signaling
Reto Guler & Frank Brombacher
doi:10.1038/nchembio.1917
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.
Full Text - Host-directed drug therapy for tuberculosis | PDF (902 KB) - Host-directed drug therapy for tuberculosis
Susanne Müller, Apirat Chaikuad, Nathanael S Gray & Stefan Knapp
doi:10.1038/nchembio.1938
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.
Full Text - The ins and outs of selective kinase inhibitor development | PDF (941 KB) - The ins and outs of selective kinase inhibitor development
Lars Iversen, Signe Mathiasen, Jannik Bruun Larsen & Dimitrios Stamou
doi:10.1038/nchembio.1941
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.
Full Text - Membrane curvature bends the laws of physics and chemistry | PDF (441 KB) - Membrane curvature bends the laws of physics and chemistry
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.
Full Text - Targeting transcription is no longer a quixotic quest | PDF (2,150 KB) - Targeting transcription is no longer a quixotic quest
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.
Full Text - XFELs open a new era in structural chemical biology | PDF (2,128 KB) - XFELs open a new era in structural chemical biology
doi:10.1038/nchembio.1820
Agreeing on a precise definition of chemical biology has been a persistent challenge for the field. We asked a diverse group of scientists to "define chemical biology" and present a selection of responses.
Full Text - Voices of chemical biology | PDF (166 KB) - Voices of chemical biology
doi:10.1038/nchembio.1845
We asked a collection of chemical biologists: "What would you say have been the most important historical contributions of chemical biology to broader areas of science"?
Full Text - Voices of chemical biology | PDF (174 KB) - Voices of chemical biology
doi:10.1038/nchembio.1880
We asked a collection of chemical biologists: "What is the most significant challenge facing chemical biology as a discipline?"
Full Text - Voices of chemical biology | PDF (164 KB) - Voices of chemical biology
doi:10.1038/nchembio.1919
We asked a collection of chemical biologists: "What do you value most about being part of the chemical biology community?"
Full Text - Voices of chemical biology | PDF (167 KB) - Voices of chemical biology
doi:10.1038/nchembio.1951
We asked a collection of chemical biologists: "What advice would you give to a junior scientist interested in pursuing a career in chemical biology?"
Full Text - Voices of chemical biology | PDF (168 KB) - Voices of chemical biology
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?"
Full Text - Voices of chemical biology | PDF (168 KB) - Voices of chemical biology
Zhong Yao, Julia Petschnigg, Robin Ketteler & Igor Stagljar
doi:10.1038/nchembio.1809
This Perspective discusses recent advances in high-throughput omics approaches such as proteomic and interactome profiling and genetic perturbations that allow the identification and alterations of cell signaling networks.
Abstract - Application guide for omics approaches to cell signaling | Full Text - Application guide for omics approaches to cell signaling | PDF (2,253 KB) - Application guide for omics approaches to cell signaling
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.
Abstract - Discovery and characterization of smORF-encoded bioactive polypeptides | Full Text - Discovery and characterization of smORF-encoded bioactive polypeptides | PDF (1,194 KB) - Discovery and characterization of smORF-encoded bioactive polypeptides
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.
Full Text - Imaging and manipulating proteins in live cells through covalent labeling | PDF (3,256 KB) - Imaging and manipulating proteins in live cells through covalent labeling
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.
Full Text - Chemical modulators of ribosome biogenesis as biological probes | PDF (1,422 KB) - Chemical modulators of ribosome biogenesis as biological probes
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.
Full Text - Progress and challenges for chemical probing of RNA structure inside living cells | PDF (1,716 KB) - Progress and challenges for chemical probing of RNA structure inside living cells
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.
Full Text - Functional genomics to uncover drug mechanism of action | PDF (1,429 KB) - Functional genomics to uncover drug mechanism of action
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