Jeyun Jo

All Publications

• Identification of covalent inhibitors of Staphylococcus aureus serine hydrolases important for virulence and biofilm formation. Nature communications Upadhyay, T., Woods, E. C., Dela Ahator, S., Julin, K., Faucher, F. F., Uddin, M. J., Hollander, M. J., Pedowitz, N. J., Abegg, D., Hammond, I., Eke, I. E., Wang, S., Chen, S., Bennett, J. M., Jo, J., Lentz, C. S., Adibekian, A., Fellner, M., Bogyo, M. 2025; 16 (1): 5046

  Abstract

  Staphylococcus aureus is a leading cause of bacteria-associated mortality worldwide. New tools are needed to both image and treat this pathogen. We previously identified a group of S. aureus serine hydrolases (Fphs), which regulate aspects of virulence and lipid metabolism. However, due to high structural and functional similarities, it remains challenging to distinguish the specific roles of members of this family. Here, we apply a high-throughput screening approach using a library of covalent electrophiles to identify inhibitors for FphB, FphE, and FphH. We identify selective covalent inhibitors for each target without the need for extensive medicinal chemistry optimization. Structural and biochemical analysis identify novel binding modes for several of the inhibitors. Functional studies using the inhibitors suggest that all three hydrolases likely play distinct functional roles in biofilm formation and virulence. This approach has the potential to be applied to target hydrolases in other diverse pathogens or higher eukaryotes.

  View details for DOI 10.1038/s41467-025-60367-3

  View details for PubMedID 40447595

  View details for PubMedCentralID 9882747

• An mRNA Display Approach for Covalent Targeting of a Staphylococcus aureus Virulence Factor. Journal of the American Chemical Society Wang, S., Woods, E. C., Jo, J., Zhu, J., Hansel-Harris, A., Holcomb, M., Llanos, M., Pedowitz, N. J., Upadhyay, T., Bennett, J., Fellner, M., Park, K. W., Zhang, A., Valdez, T. A., Forli, S., Chan, A. I., Cunningham, C. N., Bogyo, M. 2025

  Abstract

  Staphylococcus aureus (S. aureus) is an opportunistic human pathogen that causes over one million deaths around the world each year. We recently identified a family of serine hydrolases termed fluorophosphonate binding hydrolases (Fphs) that play important roles in lipid metabolism and colonization of a host. Because many of these enzymes are only expressed in Staphylococcus bacteria, they are valuable targets for diagnostics and therapeutics. Here, we developed and screened highly diverse cyclic peptide libraries using mRNA display with a genetically encoded oxadiazolone (Ox) electrophile that was previously shown to potently and covalently inhibit multiple Fph enzymes. By performing multiple rounds of counter selections with WT and catalytic dead FphB, we were able to tune the selectivity of the resulting selected cyclic peptides containing the Ox residue toward the active site serine. From our mRNA display hits, we developed potent and selective fluorescent probes that label the active site of FphB at single digit nanomolar concentrations in live S. aureus bacteria. Taken together, this work demonstrates the potential of using direct genetically encoded electrophiles for mRNA display of covalent binding ligands and identifies potent new probes for FphB that have the potential to be used for diagnostic and therapeutic applications.

  View details for DOI 10.1021/jacs.4c15713

  View details for PubMedID 40013487

• Covalent-fragment screening identifies selective inhibitors of multiple Staphylococcus aureus serine hydrolases important for growth and biofilm formation. Research square Bogyo, M., Upadhyay, T., Woods, E., Ahator, S., Julin, K., Faucher, F., Hollander, M., Pedowitz, N., Abegg, D., Hammond, I., Eke, I., Wang, S., Chen, S., Bennett, J., Jo, J., Lentz, C., Adibekian, A., Fellner, M. 2024

  Abstract

  Staphylococcus aureus is a leading cause of bacteria-associated mortality worldwide. This is largely because infection sites are often difficult to localize and the bacteria forms biofilms which are not effectively cleared using classical antibiotics. Therefore, there is a need for new tools to both image and treat S. aureus infections. We previously identified a group of S. aureus serine hydrolases known as fluorophosphonate-binding hydrolases (Fphs), which regulate aspects of virulence and lipid metabolism. However, because their structures are similar and their functions overlap, it remains challenging to distinguish the specific roles of individual members of this family. In this study, we applied a high-throughput screening approach using a library of covalent electrophiles to identify inhibitors for FphB, FphE, and FphH. We identified inhibitors that irreversibly bind to the active-site serine residue of each enzyme with high potency and selectivity without requiring extensive medicinal chemistry optimization. Structural and biochemical analysis identified novel binding modes for several of the inhibitors. Selective inhibitors of FphH impaired both bacterial growth and biofilm formation while Inhibitors of FphB and FphE had no impact on cell growth and only limited impact on biofilm formation. These results suggest that all three hydrolases likely play functional, but non-equivalent roles in biofilm formation and FphH is a potential target for development of therapeutics that have both antibiotic and anti-biofilm activity. Overall, we demonstrate that focused covalent fragment screening can be used to rapidly identify highly potent and selective electrophiles targeting bacterial serine hydrolases. This approach could be applied to other classes of lipid hydrolases in diverse pathogens or higher eukaryotes.

  View details for DOI 10.21203/rs.3.rs-5494070/v1

  View details for PubMedID 39711551

  View details for PubMedCentralID PMC11661381

• An mRNA Display Approach for Covalent Targeting of a Staphylococcus aureus Virulence Factor. bioRxiv : the preprint server for biology Wang, S., Woods, E. C., Jo, J., Zhu, J., Hansel-Harris, A., Holcomb, M., Pedowitz, N. J., Upadhyay, T., Bennett, J., Fellner, M., Park, K. W., Zhang, A., Valdez, T. A., Forli, S., Chan, A. I., Cunningham, C. N., Bogyo, M. 2024

  Abstract

  Staphylococcus aureus (S. aureus) is an opportunistic human pathogen that causes over one million deaths around the world each year. We recently identified a family of serine hydrolases termed fluorophosphonate binding hydrolases (Fphs) that play important roles in lipid metabolism and colonization of a host. Because many of these enzymes are only expressed in Staphylococcus bacteria, they are valuable targets for diagnostics and therapeutics. Here we developed and screened highly diverse cyclic peptide libraries using mRNA display with a genetically encoded oxadiazolone (Ox) electrophile that was previously shown to potently and covalently inhibit multiple Fph enzymes. By performing multiple rounds of counter selections with WT and catalytic dead FphB, we were able to tune the selectivity of the resulting selected cyclic peptides containing the Ox residue towards the desired target. From our mRNA display hits, we developed potent and selective fluorescent probes that label the active site of FphB at single digit nanomolar concentrations in live S. aureus bacteria. Taken together, this work demonstrates the potential of using direct genetically encoded electrophiles for mRNA display of covalent binding ligands and identifies potent new probes for FphB that have the potential to be used for diagnostic and therapeutic applications.

  View details for DOI 10.1101/2024.11.06.622387

  View details for PubMedID 39574702

  View details for PubMedCentralID PMC11581011

• AM-18002, a derivative of natural anmindenol A, enhances radiosensitivity in mouse breast cancer cells PLOS ONE Eum, D., Jeong, M., Park, S., Kim, J., Jin, Y., Jo, J., Shim, J., Lee, S., Park, S., Heo, K., Yun, H., Choi, Y. 2024; 19 (4): e0296989

  Abstract

  Natural anmindenol A isolated from the marine-derived bacteria Streptomyces sp. caused potent inhibition of inducible nitric oxide synthase without any significant cytotoxicity. This compound consists of a structurally unique 3,10-dialkylbenzofulvene skeleton. We previously synthesized and screened the novel derivatives of anmindenol A and identified AM-18002, an anmindenol A derivative, as a promising anticancer agent. The combination of AM-18002 and ionizing radiation (IR) improved anticancer effects, which were exerted by promoting apoptosis and inhibiting the proliferation of FM3A mouse breast cancer cells. AM-18002 increased the production of reactive oxygen species (ROS) and was more effective in inducing DNA damage. AM-18002 treatment was found to inhibit the expansion of myeloid-derived suppressor cells (MDSC), cancer cell migration and invasion, and STAT3 phosphorylation. The AM-18002 and IR combination synergistically induced cancer cell death, and AM-18002 acted as a potent anticancer agent by increasing ROS generation and blocking MDSC-mediated STAT3 activation in breast cancer cells.

  View details for DOI 10.1371/journal.pone.0296989

  View details for Web of Science ID 001205750000006

  View details for PubMedID 38625901

  View details for PubMedCentralID PMC11020960

• Development of Oxadiazolone Activity-Based Probes Targeting FphE for Specific Detection of Staphylococcus aureus Infections. Journal of the American Chemical Society Jo, J., Upadhyay, T., Woods, E. C., Park, K. W., Pedowitz, N. J., Jaworek-Korjakowska, J., Wang, S., Valdez, T. A., Fellner, M., Bogyo, M. 2024

  Abstract

  Staphylococcus aureus (S. aureus) is a major human pathogen that is responsible for a wide range of systemic infections. Since its propensity to form biofilms in vivo poses formidable challenges for both detection and treatment, tools that can be used to specifically image S. aureus biofilms are highly valuable for clinical management. Here, we describe the development of oxadiazolone-based activity-based probes to target the S. aureus-specific serine hydrolase FphE. Because this enzyme lacks homologues in other bacteria, it is an ideal target for selective imaging of S. aureus infections. Using X-ray crystallography, direct cell labeling, and mouse models of infection, we demonstrate that oxadiazolone-based probes enable specific labeling of S. aureus bacteria through the direct covalent modification of the FphE active site serine. These results demonstrate the utility of the oxadizolone electrophile for activity-based probes and validate FphE as a target for the development of imaging contrast agents for the rapid detection of S. aureus infections.

  View details for DOI 10.1021/jacs.3c13974

  View details for PubMedID 38411555

• Development of Oxadiazolone Activity-Based Probes Targeting FphE for Specific Detection of S. aureus Infections. bioRxiv : the preprint server for biology Jo, J., Upadhyay, T., Woods, E. C., Park, K. W., Pedowitz, N. J., Jaworek-Korjakowska, J., Wang, S., Valdez, T. A., Fellner, M., Bogyo, M. 2023

  Abstract

  Staphylococcus aureus is a major human pathogen responsible for a wide range of systemic infections. Since its propensity to form biofilms in vivo poses formidable challenges for both detection and treatment, tools that can be used to specifically image S. aureus biofilms are highly valuable for clinical management. Here we describe the development of oxadiazolonebased activity-based probes to target the S. aureus-specific serine hydrolase FphE. Because this enzyme lacks homologs in other bacteria, it is an ideal target for selective imaging of S. aureus infections. Using X-ray crystallography, direct cell labeling and mouse models of infection we demonstrate that oxadiazolone-based probes enable specific labeling of S. aureus bacteria through the direct covalent modification of the FphE active site serine. These results demonstrate the utility of the oxadizolone electrophile for activity-based probes (ABPs) and validate FphE as a target for development of imaging contrast agents for the rapid detection of S. aureus infections.

  View details for DOI 10.1101/2023.12.11.571116

  View details for PubMedID 38168396

  View details for PubMedCentralID PMC10760020

• Optimization of 3-aminotetrahydrothiophene 1,1-dioxides with improved potency and efficacy as non-electrophilic antioxidant response element (ARE) activators. Bioorganic & medicinal chemistry letters Jo, J., Kim, J., Ibrahim, L., Kumar, M., Iaconelli, J., Tran, C. S., Moon, H. R., Jung, Y., Wiseman, R. L., Lairson, L. L., Chatterjee, A. K., Bollong, M. J., Yun, H. 2023; 89: 129306

  Abstract

  Activating NRF2-driven transcription with non-electrophilic small molecules represents an attractive strategy to therapeutically target disease states associated with oxidative stress and inflammation. In this study, we describe a campaign to optimize the potency and efficacy of a previously identified bis-sulfone based non-electrophilic ARE activator 2. This work identifies the efficacious analog 17, a compound with a non-cytotoxic profile in IMR32 cells, as well as ARE activators 18 and 22, analogs with improved cellular potency. In silico drug-likeness prediction suggested the optimized bis-sulfones 17, 18, and 22 will likely be of pharmacological utility.

  View details for DOI 10.1016/j.bmcl.2023.129306

  View details for PubMedID 37116763