Sulfonyl fluoride electrophiles have found significant utility as reactive probes in chemical biology and molecular pharmacology. As warheads they possess the right balance of biocompatibility ...(including aqueous stability) and protein reactivity. Their functionality is privileged in this regard as they are known to modify not only reactive serines (resulting in their common use as protease inhibitors), but also context-specific threonine, lysine, tyrosine, cysteine and histidine residues. This review describes the application of sulfonyl fluoride probes across various areas of research and explores new approaches that could further enhance the chemical biology toolkit. We believe that sulfonyl fluoride probes will find greater utility in areas such as covalent enzyme inhibition, target identification and validation, and the mapping of enzyme binding sites, substrates and protein-protein interactions.
The use of sulfonyl fluoride probes in chemical biology is reviewed.
Aryl fluorosulfates are finding widespread utility in chemical biology and medicinal chemistry. The context-dependent engagement of tyrosine, lysine, serine, and histidine amino acid residues in ...functional protein sites has enabled chemogenomic and chemoproteomic techniques that demonstrate considerable promise for drug discovery and biomedical research.
Vaccines have typically been prepared using whole organisms. These are normally either attenuated bacteria or viruses that are live but have been altered to reduce their virulence, or pathogens that ...have been inactivated and effectively killed through exposure to heat or formaldehyde. However, using whole organisms to elicit an immune response introduces the potential for infections arising from a reversion to a virulent form in live pathogens, unproductive reactions to vaccine components or batch-to-batch variability. Synthetic vaccines, in which a molecular antigen is conjugated to a carrier protein, offer the opportunity to circumvent these problems. This Perspective will highlight the progress that has been achieved in developing synthetic vaccines using a variety of molecular antigens. In particular, the different approaches used to develop conjugate vaccines using peptide/proteins, carbohydrates and other small molecule haptens as antigens are compared.
New opportunities to advance small-molecule kinase ligands that downregulate their cognate target binding proteins are discussed. Rationally designed heterobifunctional kinase degraders are compared ...with ATP site ligands that were serendipitously found to cause kinase downregulation. These approaches could be particularly useful in the treatment of cancers since many kinases are known to remodel pro-oncogenic protein-protein interactions, which could be destroyed by small-molecule-mediated kinase depletion.
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The strategy of rationally designing bivalent ligands that target kinases for proteasomal degradation is compared with recent serendipitous discoveries that several monovalent ATP site kinase inhibitors are also able to downregulate their cognate binding proteins. The therapeutic prospects and challenges facing small-molecule degrader modalities are discussed.
Small molecules continue to dominate drug discovery because of their ease of use, lower cost of manufacturing, and access to intracellular targets. However, despite these advantages, small molecules ...are more likely to fail in clinical trials compared with biologicals and their development remains limited to a small subset of disease-relevant ‘druggable’ targets. Targeted protein degradation has recently emerged as a novel pharmacological modality that promises to overcome small molecule limitations whilst retaining their key advantages. Here, we use a Strengths-Weaknesses-Opportunities-Threats (SWOT) framework to critically assess the current status of this rapidly evolving field. We expect that degrader molecules are only the beginning of a range of novel targeting modalities that hijack existing endogenous cellular machineries to chemically redirect biological targets and pathways. Therefore, this piece may offer a roadmap for enhancing development of both degraders and related modalities.
Degrader molecules, small molecules that induce targeted degradation of a protein of interest, are of increasing interest in drug development and discovery.What makes degrader molecules attractive is that they offer several advantages over both small molecule inhibitors and biologics.Examples of degrader molecules that have been approved for human treatment are immunomodulatory drugs, while additional degrader molecules are undergoing clinical trials.The Strengths-Weakness-Opportunities-Threats (SWOT) analysis was used as a framework to identify key components that need to be in place to ensure accelerated future growth and prepare for some of the challenges.In our view, the field represents just the beginning of a new wave of small molecule-based modalities that act via hijacking specific elements of endogenous cellular machineries.
The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the ...identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.
The reaction of small‐molecule chemical probes with proteins has been harnessed to develop covalent inhibitor drugs and protein‐profiling technologies. This Essay discusses some of the recent ...enhancements to the chemical biology toolkit that are enabling the study of previously unchartered areas of chemoproteomic space. An analysis of the kinome is used to illustrate the potential for these approaches enable the pursuit of new targets using reactive chemical probes.
Tools of the trade: The reaction of small‐molecule chemical probes with proteins has been harnessed to develop covalent inhibitor drugs and protein‐profiling technologies. This Essay discusses some of the recent enhancements to the chemical biology toolkit that are enabling the study of previously unchartered areas of chemoproteomic space.
Squaramides are remarkable four-membered ring systems derived from squaric acid that are able to form up to four hydrogen bonds. A high affinity for hydrogen bonding is driven through a concomitant ...increase in aromaticity of the ring. This hydrogen bonding and aromatic switching, in combination with structural rigidity, have been exploited in many of the applications of squaramides. Substituted squaramides can be accessed via modular synthesis under relatively mild or aqueous conditions, making them ideal units for bioconjugation and supramolecular chemistry. In this tutorial review the fundamental electronic and structural properties of squaramides are explored to rationalise the geometry, conformation, reactivity and biological activity.
The discerning reactivity of sulfur(
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)-fluoride exchange (SuFEx) chemistry has enabled the context-specific labeling of protein binding sites by chemical probes that incorporate these versatile ...warheads. Emerging information from protein-probe structures and proteomic mapping experiments is helping advance our understanding of the protein microenvironment that dictates the reactivity of targetable amino acid residues. This review explores these new findings that should influence the future rational design of SuFEx probes for a multitude of applications in chemical biology and drug discovery.
Binding site microenvironments determine the context-dependent reactivity of sulfur(
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) fluoride-containing probes.
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