A5078945029- Click Chemistry and Applications
- Protein Degradation and Inhibitors
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Chemical Synthesis and Analysis
- RNA and protein synthesis mechanisms
- FOXO transcription factor regulation
- Signaling Pathways in Disease
- Peptidase Inhibition and Analysis
- Viral Infections and Vectors
- interferon and immune responses
- Microbial Natural Products and Biosynthesis
- Cancer-related gene regulation
- Catalytic Cross-Coupling Reactions
- CRISPR and Genetic Engineering
- Radical Photochemical Reactions
- Carbon dioxide utilization in catalysis
- Synthesis and Catalytic Reactions
- RNA Research and Splicing
- Advanced biosensing and bioanalysis techniques
- Sirtuins and Resveratrol in Medicine
- Macrophage Migration Inhibitory Factor
- Inflammasome and immune disorders
- Genomics and Chromatin Dynamics
Scripps Research Institute
2023-2024
Scripps (United States)
2022-2024
Scripps Institution of Oceanography
2022-2024
Robert Bosch (Germany)
2023
The nicotinamide adenine dinucleotide hydrolase (NADase) sterile alpha toll/interleukin receptor motif containing-1 (SARM1) acts as a central executioner of programmed axon death and is possible therapeutic target for neurodegenerative disorders. While orthosteric inhibitors SARM1 have been described, this multidomain enzyme also subject to intricate forms autoregulation, suggesting the potential allosteric modes inhibition. Previous studies identified multiple cysteine residues that support...
Abstract 5‐Methylcytosine (m 5 C) is an RNA modification prevalent on tRNAs, where it can protect tRNAs from endonucleolytic cleavage to maintain protein synthesis. The NSUN family (NSUN1‐7 in humans) of methyltransferases are capable installing the methyl group onto C position cytosines RNA. NSUNs implicated a wide range (patho)physiological processes, but selective and cell‐active inhibitors these enzymes lacking. Here, we use cysteine‐directed activity‐based profiling (ABPP) discover...
Covalent chemistry coupled with activity-based protein profiling (ABPP) offers a versatile way to discover ligands for proteins in native biological systems. Here, we describe set of stereo- and regiochemically defined spirocycle acrylamides the analysis these electrophilic "stereoprobes" human cancer cells by cysteine-directed ABPP. Despite showing attenuated reactivity compared structurally related azetidine acrylamide stereoprobes, preferentially liganded specific cysteines on diverse...
Summary Chemical proteomics enables the global assessment of small molecule-protein interactions in native biological systems and has emerged as a versatile approach for ligand discovery. The range molecules explored by chemical has, however, been limited. Here, we describe diversity-oriented synthesis (DOS)-inspired library stereochemically-defined compounds bearing diazirine alkyne units UV light-induced covalent modification click chemistry enrichment interacting proteins, respectively....
The NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines, including IL-1β IL-18. Aberrant overactivation implicated in numerous disorders. However, activation signaling remain poorly understood, limiting our ability to develop pharmacologic approaches target this complex. Here, we developed implemented high-throughput screen identify compounds that inhibit assembly activity. From screen, profile inhibition 20 new covalent...
Pioneer transcription factors (TFs) exhibit a specialized ability to bind and open closed chromatin, facilitating engagement by other regulatory involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation cells. Here, we report the chemical proteomic discovery of electrophilic small molecules that stereoselectively site-specifically TF, FOXA1, at cysteine (C258) within forkhead DNA-binding domain. We show these...
Covalent chemistry is a versatile approach for expanding the ligandability of human proteome. Activity-based protein profiling (ABPP) can infer specific residues modified by electrophilic compounds through competition with broadly reactive probes. Nonetheless, extent to which such residue-directed ABPP platforms fully assess targets in cells remains unclear. Here, we introduce complementary that directly identifies proteins showing stereoselective reactivity focused libraries...
Abstract The anti-viral and anti-cancer STING innate immune pathway can exacerbate autoimmune neurodegenerative diseases when aberrantly activated, emphasizing a key unmet need for antagonists. However, no such inhibitors have advanced to the clinic because it remains unclear which mechanistic step(s) of human activation are crucial potent context-independent inhibition downstream signaling. Here, we report that C91 palmitoylation, target tool compound, is not universally necessary...
Summary Most human proteins lack chemical probes, and several large-scale generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such “binding-first” affect protein function, nonetheless, often remains unclear. Here, we describe a “function-first” proteomic strategy that uses size exclusion chromatography (SEC) assess the global impact of electrophilic on complexes cells. Integrating SEC data with cysteine-directed activity-based...
<title>Abstract</title> The anti-viral and anti-cancer STING innate immune pathway can exacerbate autoimmune neurodegenerative diseases when aberrantly activated, emphasizing a key unmet need for antagonists. However, no such inhibitors have advanced to the clinic because it remains unclear which mechanistic step(s) of human activation are crucial potent context-independent inhibition downstream signaling. Here, we report that C91 palmitoylation, target tool compound, is not universally...
Abstract 5‐Methylcytosine (m 5 C) is an RNA modification prevalent on tRNAs, where it can protect tRNAs from endonucleolytic cleavage to maintain protein synthesis. The NSUN family (NSUN1‐7 in humans) of methyltransferases are capable installing the methyl group onto C position cytosines RNA. NSUNs implicated a wide range (patho)physiological processes, but selective and cell‐active inhibitors these enzymes lacking. Here, we use cysteine‐directed activity‐based profiling (ABPP) discover...
Boron CompoundsThesynthesis of 2,3-dihydro-2,3-diiminoboroles through regioselective double insertion isocyanide into benzoborirenes is reported by Max C