The Future of Bioorthogonal Chemistry

Bioorthogonal reactions have found widespread use in applications ranging from glycan engineering to in vivo imaging. Researchers have devised numerous reactions that can be predictably performed in a biological setting. Depending on the requirements of the intended application, one or more reactions from the available toolkit can be readily deployed. As an increasing number of investigators explore and apply chemical reactions in living systems, it is clear that there are a myriad of ways in which the field may advance. This article presents an outlook on the future of bioorthogonal chemistry. I discuss currently emerging opportunities and speculate on how bioorthogonal reactions might be applied in research and translational settings. I also outline hurdles that must be cleared if progress toward these goals is to be made. Given the incredible past successes of bioorthogonal chemistry and the rapid pace of innovations in the field, the future is undoubtedly very bright.

[1]  J. Chin,et al.  Concerted, Rapid, Quantitative, and Site-Specific Dual Labeling of Proteins , 2014, Journal of the American Chemical Society.

[2]  Carolyn R Bertozzi,et al.  Bioorthogonal chemistry: fishing for selectivity in a sea of functionality. , 2009, Angewandte Chemie.

[3]  H. Janssen,et al.  Click to release: instantaneous doxorubicin elimination upon tetrazine ligation. , 2013, Angewandte Chemie.

[4]  A. Borrmann,et al.  Highly accelerated inverse electron-demand cycloaddition of electron-deficient azides with aliphatic cyclooctynes , 2014, Nature Communications.

[5]  Andrew B. Martin,et al.  Generation of a bacterium with a 21 amino acid genetic code. , 2003, Journal of the American Chemical Society.

[6]  R. Weissleder,et al.  Unraveling Tetrazine-Triggered Bioorthogonal Elimination Enables Chemical Tools for Ultrafast Release and Universal Cleavage , 2018, Journal of the American Chemical Society.

[7]  Dariusz Matosiuk,et al.  Click chemistry for drug development and diverse chemical-biology applications. , 2013, Chemical reviews.

[8]  Jie Li,et al.  Bioorthogonal Chemical Activation of Kinases in Living Systems , 2016, ACS central science.

[9]  R. Rossin,et al.  Highly reactive trans-cyclooctene tags with improved stability for Diels-Alder chemistry in living systems. , 2013, Bioconjugate chemistry.

[10]  Jason S. Lewis,et al.  Establishment of the In Vivo Efficacy of Pretargeted Radioimmunotherapy Utilizing Inverse Electron Demand Diels-Alder Click Chemistry , 2016, Molecular Cancer Therapeutics.

[11]  Qing Lin,et al.  Sterically Shielded, Stabilized Nitrile Imine for Rapid Bioorthogonal Protein Labeling in Live Cells. , 2018, Journal of the American Chemical Society.

[12]  N. Devaraj,et al.  Traceless synthesis of ceramides in living cells reveals saturation-dependent apoptotic effects , 2018, Proceedings of the National Academy of Sciences.

[13]  D. Tirrell,et al.  Presentation and detection of azide functionality in bacterial cell surface proteins. , 2004, Journal of the American Chemical Society.

[14]  Carolyn R. Bertozzi,et al.  Copper-free click chemistry for dynamic in vivo imaging , 2007, Proceedings of the National Academy of Sciences.

[15]  N. Devaraj,et al.  Membrane assembly driven by a biomimetic coupling reaction. , 2012, Journal of the American Chemical Society.

[16]  N. Devaraj,et al.  Live-cell imaging of cyclopropene tags with fluorogenic tetrazine cycloadditions. , 2012, Angewandte Chemie.

[17]  T. Muir,et al.  Synthesis of proteins by native chemical ligation. , 1994, Science.

[18]  R. Rossin,et al.  SYNFORM ISSUE 2010/9 , 2010, Angewandte Chemie.

[19]  R. Weissleder,et al.  Biomedical applications of tetrazine cycloadditions. , 2011, Accounts of chemical research.

[20]  T. Heightman,et al.  Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras , 2016, ACS central science.

[21]  C. Meares,et al.  Pre-targeted immunoscintigraphy of murine tumors with indium-111-labeled bifunctional haptens. , 1988, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[22]  Haoxing Wu,et al.  A Bioorthogonal Near-Infrared Fluorogenic Probe for mRNA Detection. , 2016, Journal of the American Chemical Society.

[23]  J. Campagne,et al.  Nonclassical Routes for Amide Bond Formation. , 2016, Chemical reviews.

[24]  C. Bertozzi,et al.  Systemic Fluorescence Imaging of Zebrafish Glycans with Bioorthogonal Chemistry. , 2015, Angewandte Chemie.

[25]  R. Weissleder,et al.  A Pretargeted PET Imaging Strategy Based on Bioorthogonal Diels–Alder Click Chemistry , 2013, The Journal of Nuclear Medicine.

[26]  Greg M. Thurber,et al.  Reactive polymer enables efficient in vivo bioorthogonal chemistry , 2012, Proceedings of the National Academy of Sciences.

[27]  B. Oliveira,et al.  Vinyl Ether/Tetrazine Pair for the Traceless Release of Alcohols in Cells , 2016, Angewandte Chemie.

[28]  Jennifer A. Prescher,et al.  Orthogonal bioorthogonal chemistries. , 2015, Current opinion in chemical biology.

[29]  I. Hamachi,et al.  Live-Cell Protein Sulfonylation Based on Proximity-driven N-Sulfonyl Pyridone Chemistry. , 2018, Angewandte Chemie.

[30]  Annamaria Lilienkampf,et al.  Tetrazine‐Responsive Self‐immolative Linkers , 2017, Chembiochem : a European journal of chemical biology.

[31]  R. Raines,et al.  High-yielding Staudinger ligation of a phosphinothioester and azide to form a peptide. , 2001, Organic letters.

[32]  Dyeison Antonow Fragment-based approaches and the prospect of fragmented prodrugs. , 2010, Drug discovery today.

[33]  D. Rideout Self-assembling cytotoxins. , 1986, Science.

[34]  J. Bode,et al.  Rapid ligations with equimolar reactants in water with the potassium acyltrifluoroborate (KAT) amide formation. , 2014, Journal of the American Chemical Society.

[35]  H. Janssen,et al.  DOTA-tetrazine probes with modified linkers for tumor pretargeting. , 2017, Nuclear medicine and biology.

[36]  R. Kleiman,et al.  Cyclopropene fatty acids of selected seed oils from bombacaceae, malvaceae, and sterculiaceae , 1978, Lipids.

[37]  Ivana Nikić,et al.  Highly Stable trans-Cyclooctene Amino Acids for Live-Cell Labeling. , 2015, Chemistry.

[38]  N. Devaraj,et al.  Fluorescent Live‐Cell Imaging of Metabolically Incorporated Unnatural Cyclopropene‐Mannosamine Derivatives , 2013, Chembiochem : a European journal of chemical biology.

[39]  R. Weissleder,et al.  Bioorthogonal reaction pairs enable simultaneous, selective, multi-target imaging. , 2012, Angewandte Chemie.

[40]  R. Weissleder,et al.  Tetrazine-based cycloadditions: application to pretargeted live cell imaging. , 2008, Bioconjugate chemistry.

[41]  T. Brown,et al.  Synthesis and polymerase chain reaction amplification of DNA strands containing an unnatural triazole linkage. , 2009, Journal of the American Chemical Society.

[42]  C. Bertozzi,et al.  A "traceless" Staudinger ligation for the chemoselective synthesis of amide bonds. , 2000, Organic letters.

[43]  B. Wang,et al.  Click and Release: A Chemical Strategy toward Developing Gasotransmitter Prodrugs by Using an Intramolecular Diels-Alder Reaction. , 2016, Angewandte Chemie.

[44]  Ralph Weissleder,et al.  Fast and sensitive pretargeted labeling of cancer cells through a tetrazine/trans-cyclooctene cycloaddition. , 2009, Angewandte Chemie.

[45]  R. Franzini,et al.  Rapid and efficient tetrazine-induced drug release from highly stable benzonorbornadiene derivatives. , 2017, Chemical communications.

[46]  Jennifer A. Prescher,et al.  A comparative study of bioorthogonal reactions with azides. , 2006, ACS chemical biology.

[47]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[48]  J. Ohlrogge,et al.  Carbocyclic fatty acids in plants: Biochemical and molecular genetic characterization of cyclopropane fatty acid synthesis of Sterculia foetida , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Joseph M. Fox,et al.  Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity. , 2008, Journal of the American Chemical Society.

[50]  Chi-Huey Wong,et al.  In situ click chemistry: enzyme-generated inhibitors of carbonic anhydrase II. , 2004, Angewandte Chemie.

[51]  M. Royzen,et al.  In Vivo Bioorthogonal Chemistry Enables Local Hydrogel and Systemic Pro-Drug To Treat Soft Tissue Sarcoma , 2016, ACS central science.

[52]  Jennifer A. Prescher,et al.  1,2,4-Triazines Are Versatile Bioorthogonal Reagents. , 2015, Journal of the American Chemical Society.

[53]  Peter G Schultz,et al.  A phage display system with unnatural amino acids. , 2004, Journal of the American Chemical Society.

[54]  P. Taylor,et al.  Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. , 2002, Angewandte Chemie.

[55]  Anne‐Katrin Späte,et al.  Rapid labeling of metabolically engineered cell-surface glycoconjugates with a carbamate-linked cyclopropene reporter. , 2014, Bioconjugate chemistry.

[56]  Peng R. Chen,et al.  Diels-Alder reaction-triggered bioorthogonal protein decaging in living cells. , 2014, Nature chemical biology.

[57]  Han-jie Zhang,et al.  Rapid, Stoichiometric, Site-Specific Modification of Aldehyde-Containing Proteins Using a Tandem Knoevenagel-Intra Michael Addition Reaction. , 2018, Bioconjugate chemistry.

[58]  O. Seitz,et al.  DNA-triggered synthesis and bioactivity of proapoptotic peptides. , 2011, Angewandte Chemie.

[59]  William Lindstrom,et al.  Inhibitors of HIV-1 protease by using in situ click chemistry. , 2006, Angewandte Chemie.

[60]  W. Linehan,et al.  Co-opting a Bioorthogonal Reaction for Oncometabolite Detection. , 2016, Journal of the American Chemical Society.

[61]  S B Jennifer Kan,et al.  Enzymatic construction of highly strained carbocycles , 2018, Science.

[62]  Jennifer A. Prescher,et al.  Functionalized cyclopropenes as bioorthogonal chemical reporters. , 2012, Journal of the American Chemical Society.

[63]  Alejandro Méndez‐Ardoy,et al.  Design and synthesis of a "click" high-mannose oligosaccharide mimic emulating Man8 binding affinity towards Con A. , 2012, Chemical communications.

[64]  J. Chin,et al.  Rapid and Efficient Generation of Stable Antibody–Drug Conjugates via an Encoded Cyclopropene and an Inverse‐Electron‐Demand Diels–Alder Reaction , 2018, Angewandte Chemie.

[65]  C. Bertozzi A decade of bioorthogonal chemistry. , 2011, Accounts of chemical research.

[66]  Chong Yu,et al.  A metabolic labeling approach toward proteomic analysis of mucin-type O-linked glycosylation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[67]  R. Raines,et al.  Diazo Groups Endure Metabolism and Enable Chemoselectivity in Cellulo , 2015, Journal of the American Chemical Society.

[68]  C. Bertozzi,et al.  In Vivo Imaging of Membrane-Associated Glycans in Developing Zebrafish , 2008, Science.

[69]  C. Bertozzi,et al.  From Mechanism to Mouse: A Tale of Two Bioorthogonal Reactions , 2011, Accounts of chemical research.