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feature Voices of chemical We asked a collection of chemical , “What is the most exciting frontier area in and what key technology is needed to advance knowledge and applications in this area?” and reveal some of the perspectives we received.

am glad to see that people are being If we could design efficient artificial modifications (PTMs) were installed and increasingly bold in building complex for any of how they execute their functions on a Ibiological constructs and viewing ‘editing’ interest, it would open the door to a wide molecular level. Tools that enable PTM of biology as being within our with range of applications in chemical biology. To mapping in living cells with spatial and even potentially therapeutic application. advance knowledge and application in this temporal resolution could provide insights Organismal editing, if coupled with ‘deep’ area, I believe it will be essential to design into which modifications have meaningful (appropriately sensitive) mechanistic all intermediates along the reaction phenotypic consequences and would allow us (to obtain quantitative coordinate instead of solely focusing on the to develop a molecular-level understanding measurements on complex, endogenous transition state, as has been done in the past. of what those consequences are. For substrates) might enable not only direct Roberto Chica example, targeting PTM capture tools to tracking of the multiple effects of, say, University of Ottawa, Ottawa, Ontario, specific subcellular locations would enable but also in vivo to edit, Canada generation of spatially resolved PTM maps modulate and/or perturb such pathways. that would shed light on how PTMs impact Benjamin Davis The interplay between metabolites and localization. This information would The Rosalind Franklin Institute, provides an important layer for the allow us to functionally prioritize PTMs Oxfordshire, UK regulation of membraneless compartments in for follow-up experiments and to dissect cells, but this has been poorly explored. The previously unappreciated functional nodes in The intersection of and systematic identification and exploration of biological signaling pathways. chemical biology is an exciting emerging biological metabolites that regulate protein Amy Weeks area poised to take off over the next five phase separation may inspire chemical University of Wisconsin. Madison, WI, years. In particular, the development of intervention to strengthen functional USA new tools and techniques that can globally membraneless compartmentation. map the dynamics of protein–protein Dan Li The restoration of structural stability and and protein–RNA interactions and gain Shanghai Jiao Tong University, Shanghai, hence of an essential protein insights into the functions and therapeutic China rendered deficient by a single amino acid relevance of these interactions is a key remains extremely challenging. unmet challenge for chemical biologists. In establishing microbial factories for Understanding the biology of a system can Such interatomic studies will almost the production of natural chemicals, there inform small- drug development undoubtedly require technical innovations are often unknown enzymes within the to rescue defective proteins or enhance the in both chemical and photo-crosslinkers, biosynthetic pathway, which is particularly activity of endogenous normally encoded including for small-molecule and true for complex natural products. For proteins. Thus, the potential of molecular crosslinking . Innovations non-natural chemicals, there are often no correctors to act as nanoprosthetics, while in data analysis and data integration are also known enzymes at all for some conversion challenging, can be highly rewarding. going to be essential. steps. Thus, rapid, accurate, and efficient Christopher Overall Keri Backus design, engineering, and even creation University of British Columbia, Vancouver, University of California, Los Angeles, Los of necessary enzymes is the single most Canada Angeles, CA, USA important technology needed by metabolic engineers. researchers have been spending a lot I am particularly excited about the Sang Yup Lee of time producing with desired traits. possibilities offered by functional . KAIST, Daejeon, Republic of Korea This could be shortened by chemical biology Dramatic advances in the field of synthetic approaches that identify that can biology and highly multiplexed DNA We are entering an era of ‘human chemical regulate physiological functions of plants, synthesis will allow us to interrogate biology’ in which will need to leading to efficient and sustainable food gene products at a single amino acid develop new genomics, proteomics, imaging production. resolution with unprecedented speed and tools and selective small-molecule probes Shinya Hagihara scale. Intersecting this type of data with to directly study human samples in a RIKEN Center for Sustainable modern-day docking studies should advance non-invasive manner to understand disease Science, Saitama, Japan our understanding and serve as a highly biology and patient-derived systems. valuable and probably faster alternative to Chuan He The wealth of we’ve inherited structural elucidation. University of Chicago, Chicago, IL, USA from is enormous, but we Georg Winter shouldn’t stop there! We need to reach past CeMM Research Center for Molecular We need to develop new technologies that off-the-shelf components to build our own of the Austrian Academy of will enable us to ask, on a proteome-wide biological systems. Chemical biology needs to Sciences, Vienna, Austria scale, why specific post-translational develop its emerging interplay with synthetic

Nature Chemical Biology | VOL 17 | January 2021 | 1–4 | www..com/naturechemicalbiology 1 feature biology into a symbiosis toward making new I think the integration of glycans into our The next frontier will be to devise molecules parts, including new functional understanding of proteins and is and methods that enable the complexity with capabilities not already found in nature. still the most exciting frontier in chemical and heterogeneity of biological mechanisms In my opinion, the less distinction we make biology. We have so much to learn and still within living cells or tissues to be between ‘chemical’ and ‘synthetic’ biology, the need better tools to consider the impacts of interrogated and mapped with higher spatial more we can all accomplish. one on the other. and temporal resolution than is currently Ben Thuronyi Lara K. Mahal possible. To achieve this we will need clever Williams College, Williamstown, MA, University of Alberta, Alberta, Canada designs of small molecules that are able USA to bind and modulate macromolecular Imagine a single place where you could conformations in vivo and physical methods A large fraction of our proteome remains send a sample and they send you back capable of tracking the interactions of uncharacterized in terms of its biological everything that is happening in the cells molecules with near-atomic resolution in function in health and disease. Therefore, in a form that is easily interpretable and real time in situ. mechanistically understanding the rapidly guides the next round of design. This Sheena Radford biochemical, molecular and cellular type of whole-cell debugging is crucial; we University of Leeds, Leeds, UK functions of such unannotated proteins need to comprehensively ‘see’ the effects of (enzymes) represents a grand challenge engineering on the cell. Unravelling the functional roles of novel and a daunting task to modern chemical Christopher Voigt histone marks in epigenetic regulation is biologists. Obtaining this new information Massachusetts Institute of Technology, still the most exciting frontier area that can lead to valuable new that Cambridge, MA, USA can be advanced by the chemical biology may facilitate early diagnosis of diseases . To advance our understanding or novel therapeutic paradigms in their Similar to recent advances demonstrating of these histone modifications, it is treatment and/or clinical management. the ability to alter specific genetic essential to identify the enzymes that Siddhesh Kamat modifications, dialing in post-translational add (‘write’) and remove (‘erase’) the Indian Institute of Science Education and modifications on proteins seems possible. marks and ‘reader’ proteins that interpret Research, Pune, India Mass spectrometry and chemical proteomics them. To address this challenge, technology will play a big technological role, as it’s one that allows the detection or capture of One of the most exciting frontier areas is the of the few ways to directly measure protein histone PTM-mediated protein–protein continued development of RNA chemical modifications. To fully enable this capability, interactions needs to be developed. In biology-based ideas and approaches, as we will have to innovate new methods in addition, nucleosome- and - advanced and robust tools are still needed chemical biology, which is the exciting part! based chemical biology tools can also to study and engineer RNA. In particular, Christina Woo provide a useful strategy to investigate capturing RNA and ribonucleoproteins Harvard University, Cambridge, MA, USA the crosstalk of histone modifications in situ within certain subcellular compart­ within a nucleosome or between different ments in cells followed by spatiotemporal Cellular —the playing field of nucleosomes. visualization with super-resolution imaging much of chemical biology research—would Xiang David Li systems to cryo-technology revolutionized reveal many secrets if we could detect The University of Hong Kong, Hong Kong, tomography will provide new insights metabolite levels and their fluctuations in China into how RNA plays a role in organizing subcellular compartments and with membraneless cellular granules. high levels of confidence. Such analytical tools I think the most exciting frontier area is Ling-Ling Chen are key to understanding a range of diseases molecular optogenetics controlling Shanghai Institute of and such as , neurodegeneration and aging. specific molecules in living cells. Through Cell Biology, Shanghai, China Erick Strauss the new generation of optogenetic tools, Stellenbosch University, Stellenbosch, we can better understand Using cryo-EM to obtain the South Africa and cellular functions in living cells of protein complexes and medium–large and . individual proteins and enzymes will inform We need to develop comprehensive, efficient Won Do Heo how these complex systems function at a and rational technology that enables delivery KAIST, Daejeon, Republic of Korea molecular level. To accomplish this, new and of molecules to a precise cellular . more affordable microscopes and automatic Kazuya Kikuchi The realization that drugs can confer new computational methodologies will be Osaka University, Osaka, Japan properties to the proteins they engage has required, which will in turn make cryo-EM opened up a new dimension to chemical affordable and accessible to everyone. For new therapeutic modalities, such as biology. In particular, small molecules Ramón Hurtado Guerrero targeted protein degradation, and new can ‘massage’ proteins, creating large but University of Zaragoza, Zaragoza, Spain target types, such as RNA and biomolecular also very subtle changes that can alter the condensates, chemical biologists will need protein’s social properties, from inducing a We need to develop highly efficient to design and synthesize the molecular tiny twist to efficiently engage an E3 ligase technology that enables efficient cell and tools necessary to enable development of to short-circuiting two pathways. Even delivery of protein–DNA–RNA the theories and paradigms that will guide molecules with low affinity for their targets complexes with cell-type or tissue specificity the drug-discovery process toward the can now achieve great things. and minimal endosomal trapping. successful launch of new . Giulio Superti-Furga Shao Yao Timothy Dore CeMM Research Center for Molecular National University of Singapore, NYU Abu Dhabi, Abu Dhabi, United Arab Medicine of the Austrian Academy of Singapore, Singapore Emirates Sciences, Vienna, Austria

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Imagine if we could peer into the human The new frontier in drug discovery will can be extremely long lived. Even though to better understand the molecular be a merging of the two fields ‘molecular switching between long-lived functional interactions and mechanisms that take place glues’ and heterobifunctional degraders modes appears to be a ubiquitous property in various physiological states. Equipped to enable the design of interfacial binders. of polypeptides and polynucleotides, its with the tools derived from chemical biology We may be able to drug protein complexes biological relevance has been unclear. I to facilitate the analysis of single cells in that normally interact with one another in believe that mode switching will emerge as their natural environment, will a cell or create de novo protein complexes a generic mechanism for protein regulation. be able to answer long-standing biological using small-molecule interfacial binders. Investigating these phenomena requires questions about aging, the mediators of The future is one where we view targets not functional assays able to directly observe disease and the threshold requirements of as stand-alone entities but as one half of single molecules for hours, including cells and molecules that change healthy an interface that could be directed to any millions of individual functional events. states to diseased states. number of factors in a cell to activate, inhibit Dimitrios Stamou Tara Deans or degrade. The possibilities are endless! University of Copenhagen, Copenhagen, University of Utah, Salt Lake City, UT, Shiva Malek Denmark USA Genentech, South San Francisco, CA, USA I hope that we will be able to know more I think the most exciting area in chemical While small-molecule modulation of protein about the sequence–structure–function biology is the development of tools that activity is a pillar of chemical biology relationships that allow us to accurately allow us to monitor and modulate cellular research, the equivalent for the predict molecular interactions and reaction functions and cell fate. Monitoring requires world is only beginning to be discovered by enzymes and ultimately to the development of imaging probes, and used. A true frontier will be to develop modify sequences to change chemical synthetic or genetically encoded, to trace potent and specific small molecules that output. To realize this aim, we need to processes in living cells and chemical tags target small nucleic acids, but not proteins. develop the capability to test the output of a that allow omics identification of particular Herbert Waldmann large number of sequence variations using molecules and their modifications. Max Planck Institute for Molecular sensitive and tailored detection techniques. Modulation reflects our ability to , Dortmund, Germany Emily Parker selectively tune pathways and metabolites Victoria University of Wellington, in cells, in space and in time to understand Detailed understanding of how a Wellington, New Zealand how they affect functioning of the cells, polypeptide chain folds into the tissues and organs. three-dimensional structure of a mature Recently, chemical biology has been moving Vsevolod Belousov protein is an important and fundamental toward the quantum world, and our capacity Shemyakin-Ovchinnikov Institute of topic that still remains poorly understood. to appreciate time-resolved dynamics of , Moscow, Russia The key to this knowledge lies in basic biological such as those protein-folding principles and, perhaps most in biocatalysis is mostly underpinned on I think the next frontier will involve importantly, in the behavior of proteins in first-principles simulations. In this discovering new chemistry de novo and their natural environment. Machine learning scenario, experimental quantum chemical in vivo. The key technology is proteomics methods can give us tools to increase our biology and disruptive imaging methods and deploying it in new ways that enable understanding and predict these events, will emerge, providing a further level of different ways of thinking about the data and while wet-lab technologies will enable us to molecular understanding of biological how we define chemical probes. Coupling study proteins and other macromolecules at systems. target discovery to lead compounds that atomic resolution in their natural, crowded Mario Murakami operate by new mechanisms is where we environment. Brazilian Center for Research in can do better. Anna Rising and Materials, São Paulo, Brazil Megan Matthews Karolinska Institutet, Stockholm, Sweden University of Pennsylvania, Philadelphia, To me, the most exciting frontier in chemical PA, USA New technologies are emerging that biology is bridging living and non-living will transform our ability to engineer systems for biotechnology applications. Proteins and peptides have so much to manufacture new classes of Hybrid systems such as , which potential as tools, therapeutics, sensors and enzymes, therapeutics and materials with incorporate living cells or organelles as industrial catalysts. Our ability to design diverse genetically encoded chemistry. functional elements, allow us to capitalize on them to suit our needs, rather than use or I, for one, look forward to advances that the strengths of both biology and chemistry. tinker with what nature has provided, has enable -mediated polymerization Like any research area that is pushing the enormous potential. We are already seeing of biopolymers containing exclusively boundaries of knowledge, the key necessary an interesting convergence of inexpensive mirror-image and backbone-extended technologies are analytical capabilities that DNA synthesis and robotics-based amino acids. Such polymers could allow us to have a detailed understanding of high-throughput screening with energy accelerate the discovery of next-generation the behavior of these hybrid systems across function-based design and machine learning. therapeutics and materials. time with high spatial resolution. However, all of these new techniques will Michael Jewett Karen Polizzi only take us as far as our fundamental Northwestern University, Evanston, Imperial College London, London, UK understanding of protein structure, function Illinois, USA and dynamics allows us to go. The development of useful chemical– Colin Jackson Single-molecule experiments have revealed and genome-editing tools coupled Australian National University, Canberra, that the function of biological molecules with new imaging strategies will help Australia fluctuates over time, and such fluctuations visualize target molecules and events with

Nature Chemical Biology | VOL 17 | January 2021 | 1–4 | www.nature.com/naturechemicalbiology 3 feature high resolution in vivo, which is crucial in molecules whose actions are governed developmental achievements during understanding brain functions and disorders outside of the lock-and-key theory could evolution. in a quantitative manner. exert biological activities beyond our current Roberto Solano Itaru Hamachi imagination. Such discovery would require Centro Nacional de Biotecnologia-CSIC, Kyoto University, Kyoto, Japan further development of chemical libraries Madrid, Spain beyond the rule of five and new simple The most exciting current development in technologies for direct identification of Protein biochemistry benefits from a chemical biology is our increasing ability non-protein targets. rich toolkit. I look forward to chemical to design and engineer complex biological Motonari Uesugi biology breakthroughs thatwill transform systems from the bottom up. This will Kyoto University, Kyoto, Japan our understanding of regulation of other transform biology from an analytical into macromolecules, especially lipids and a truly synthetic discipline. We will be able The most exciting work I see in this area metabolites. I anticipate great advances from to create a whole new world of biological is describing novel binders and modulators improved detection and quantification (e.g., systems that feature completely novel of nodal signaling protein–protein through emerging Raman imaging and mass chemistries yet retain the properties of interactions. spectrometry methods) to the identification living systems. These human-made chemical Rab Prinjha of biosynthetic pathways in understudied biological systems will provide alternative, GlaxoSmithKline, Stevenage, and presently unknown . more efficient solutions to natural processes Hertfordshire, UK Brenda Schulman or perform tasks not found in natural Max Planck Institute of Biochemistry, systems and thus could find applications in The available methodologies for mapping Martinsried, Germany virtually all technological fields, including and quantification of epitranscriptomic , biotechnology and marks in low abundance RNA are far Chemical biology is pioneering a new bridge medicine. from perfect. A desirable technology, between academia and industry. Given Tobias Erb with the potential to significantly advance the complexity of biology, strengthening Max Planck Institute for Terrestrial epitranscriptomics research and derived collaborations between industry and , Marburg, Germany applications, is high-throughput direct academic laboratories is going to be key over sequencing of RNA, which will allow the next five years to continue this upward An ultrasensitive technique such as analysis of single long RNA molecules and trajectory. We believe that chemical biology single-molecule protein sequencing is sensitive and reliable identification of can serve as a powerful interface between needed. This opens exciting new frontiers modifications. academia and industry that facilitates the to answer questions that we might not Gidi Rechavi synergistic impact on both our fundamental even know of yet and in doing so will Sheba Cancer Research Center, Tel Aviv, understanding of pathological events as well revolutionize the fields of medicine, Israel as our capacity to treat them. agriculture, and beyond. Yael David Chirlmin Joo The challenge now is to expand progress Memorial Sloan Kettering Medical Center, Delft University of Technology, Delft, The in genomic, proteomic and metabolomic New York, NY, USA Netherlands data to evolutionary chemical biology. The Rob Oslund conservation of small-molecule–orthologue Merck Exploratory Science Center, Synthetic molecules, whether small or large, protein interactions in phylogenetically Cambridge, MA, USA should be capable of executing most or even distant species suggests the importance of all of a protein’s tasks if they are designed particular interactions, which, combined Published online: 16 December 2020 or explored well. Undrug-like synthetic with omics data, may be correlated with https://doi.org/10.1038/s41589-020-00714-1

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