Jiyong Hong

Overview:

Research in the Hong group focuses on using chemical tools, in particular small molecules, to understand the signaling pathways in biology. We synthesize biologically interesting natural products and screen small molecule libraries to identify modulators of biological processes. Then, we explore their modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. In addition, we design and develop unique and efficient synthetic strategies that will allow rapid access to molecular complexity and structural diversity. Through multidisciplinary approaches, including organic synthesis, molecular biology, and cell biology, the cellular components and molecular events that embody cancer, immune response, and GPCR signaling have systematically been explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases.

  1. Synthesis of Natural Products and Study of Mode of Action: We synthesize biologically interesting natural products and explore the modes of action in order to investigate intracellular signaling pathways and identify novel targets for drug design. Completed target molecules include largazole (a marine natural product with HDAC inhibitory activity), brasilibactin A (a cytotoxic siderophore), manassantins A and B (natural products with anti-HIF-1 activity), and subglutinols A and B (natural products with immunosuppressive activity).
  2. Development of Novel Synthetic Methodology: We design and develop unique and efficient synthetic strategies which will allow rapid access to molecular complexity and structural diversity. A specific area of interest includes the development of novel methods for the stereoselective synthesis of substituted tetrahydrofurans and tetrahydropyrans.
  3. Screen of Small Molecule Libraries for Identification of Small Molecule Modulators of Biological Processes: With the advent of combinatorial chemistry and other synthetic technologies, it is feasible to prepare large collections of synthetic organic molecules. These libraries are useful in providing molecules that can be used to probe relevant biological pathways. We are interested in identification of modulators of biological processes, including drug abuse and neurodegenerative diseases.

Through multidisciplinary approaches, the cellular components and molecular events that embody cancer, immune response, and neurodegenerative diseases are systematically explored. Compounds employed in these studies could also advance the development of novel therapeutics for the treatment of human diseases.

Positions:

Professor of Chemistry

Chemistry
Trinity College of Arts & Sciences

Associate Chair of Chemistry

Chemistry
Trinity College of Arts & Sciences

Associate Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1993

Seoul National University (South Korea)

M.S. 1995

Seoul National University (South Korea)

Ph.D. 2001

The Scripps Research Institute

Grants:

Human Stringent Response as Novel Therapeutic Approaches for Breast Cancers

Administered By
Molecular Genetics and Microbiology
Awarded By
Department of Defense
Role
Co Investigator
Start Date
End Date

Biosynthesis of peptidyl nucleoside antifungal antibiotics

Administered By
Biochemistry
Awarded By
National Institutes of Health
Role
Collaborating Investigator
Start Date
End Date

PKC zeta-Specific Inhibitors for Treatment of Methamphetamine Addiction

Administered By
Chemistry
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Interrogating the cholinergic basis of opioid reinforcement with subcellular precision

Administered By
Biomedical Engineering
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Structural Biological Development of Fungal-Specific Calcineurin Inhibitors

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Publications:

Synthetic efforts toward the bicyclo[3.2.1]octane fragment of rhodojaponin III

Rhodojaponin III is a grayanane-type diterpenoid natural product with a novel chemical scaffold. It shows potent antinociceptive activity and may represent a new class of natural non-opioid analgesics with a novel mode of action. We explored the Au(I)-catalyzed Conia-ene cyclization and the Mn(III)-mediated radical cyclization of alkynyl ketones for the synthesis of the bicyclo[3.2.1]octane fragment of rhodojaponin III. These strategies will be applicable in the synthesis of rhodojaponin III and analogs for future biological studies.
Authors
Webster, CG; Park, H; Ennis, AF; Hong, J
MLA Citation
Webster, C. G., et al. “Synthetic efforts toward the bicyclo[3.2.1]octane fragment of rhodojaponin III.” Tetrahedron Letters, vol. 71, May 2021. Scopus, doi:10.1016/j.tetlet.2021.153055.
URI
https://scholars.duke.edu/individual/pub1480734
Source
scopus
Published In
Tetrahedron Letters
Volume
71
Published Date
DOI
10.1016/j.tetlet.2021.153055

Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria.

Bacterial infections caused by multi-drug-resistant Gram-negative pathogens pose a serious threat to public health. Gram-negative bacteria are characterized by the enrichment of lipid A-anchored lipopolysaccharide (LPS) or lipooligosaccharide (LOS) in the outer leaflet of their outer membrane. Constitutive biosynthesis of lipid A via the Raetz pathway is essential for bacterial viability and fitness in the human host. The inhibition of early-stage lipid A enzymes such as LpxC not only suppresses the growth of Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter spp., and other clinically important Gram-negative pathogens but also sensitizes these bacteria to other antibiotics. The inhibition of late-stage lipid A enzymes such as LpxH is uniquely advantageous because it has an extra mechanism of bacterial killing through the accumulation of toxic lipid A intermediates, rendering LpxH inhibition additionally lethal to Acinetobacter baumannii. Because essential enzymes of the Raetz pathway have never been exploited by commercial antibiotics, they are excellent targets for the development of novel antibiotics against multi-drug-resistant Gram-negative infections.This Account describes the ongoing research on characterizing the structure and inhibition of LpxC and LpxH, the second and fourth enzymes of the Raetz pathway of lipid A biosynthesis, in the laboratories of Dr. Pei Zhou and Dr. Jiyong Hong at Duke University. Our studies have elucidated the molecular basis of LpxC inhibition by the first broad-spectrum inhibitor, CHIR-090, as well as the mechanism underlying its spectrum of activity. Such an analysis has provided a molecular explanation for the broad-spectrum antibiotic activity of diacetylene-based LpxC inhibitors. Through the structural and biochemical investigation of LpxC inhibition by diacetylene LpxC inhibitors and the first nanomolar LpxC inhibitor, L-161,240, we have elucidated the intrinsic conformational and dynamics difference in individual LpxC enzymes near the active site. A similar approach has been taken to investigate LpxH inhibition, leading to the establishment of the pharmacophore model of LpxH inhibitors and subsequent structural elucidation of LpxH in complex with its first reported small-molecule inhibitor based on a sulfonyl piperazine scaffold.Intriguingly, although our crystallographic analysis of LpxC- and LpxH-inhibitor complexes detected only a single inhibitor conformation in the crystal lattice, solution NMR studies revealed the existence of multiple ligand conformations that together delineate a cryptic ligand envelope expanding the ligand-binding footprint beyond that observed in the crystal structure. By harnessing the ligand dynamics information and structural insights, we demonstrate the feasibility to design potent LpxC and LpxH inhibitors by merging multiple ligand conformations. Such an approach has enabled us to rationally design compounds with significantly enhanced potency in enzymatic assays and outstanding antibiotic activities in vitro and in animal models of bacterial infection. We anticipate that continued efforts with structure and ligand dynamics-based lead optimization will ultimately lead to the discovery of LpxC- and LpxH-targeting clinical antibiotics against a broad range of Gram-negative pathogens.
Authors
MLA Citation
Zhou, Pei, and Jiyong Hong. “Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria.Acc Chem Res, vol. 54, no. 7, Apr. 2021, pp. 1623–34. Pubmed, doi:10.1021/acs.accounts.0c00880.
URI
https://scholars.duke.edu/individual/pub1476489
PMID
33720682
Source
pubmed
Published In
Acc Chem Res
Volume
54
Published Date
Start Page
1623
End Page
1634
DOI
10.1021/acs.accounts.0c00880

Synthesis and evaluation of cyclopentane-based muraymycin analogs targeting MraY.

Antibiotic resistance is one of the most challenging global health issues and presents an urgent need for the development of new antibiotics. In this regard, phospho-MurNAc-pentapeptide translocase (MraY), an essential enzyme in the early stages of peptidoglycan biosynthesis, has emerged as a promising new antibiotic target. We recently reported the crystal structures of MraY in complex with representative members of naturally occurring nucleoside antibiotics, including muraymycin D2. However, these nucleoside antibiotics are synthetically challenging targets, which limits the scope of medicinal chemistry efforts on this class of compounds. To gain access to active muraymycin analogs with reduced structural complexity and improved synthetic tractability, we prepared and evaluated cyclopentane-based muraymycin analogs for targeting MraY. For the installation of the 1,2-syn-amino alcohol group of analogs, the diastereoselective isocyanoacetate aldol reaction was explored. The structure-activity relationship analysis of the synthesized analogs suggested that a lipophilic side chain is essential for MraY inhibition. Importantly, the analog 20 (JH-MR-23) showed antibacterial efficacy against Staphylococcus aureus. These findings provide insights into designing new muraymycin-based MraY inhibitors with improved chemical tractability.
Authors
Kwak, S-H; Lim, WY; Hao, A; Mashalidis, EH; Kwon, D-Y; Jeong, P; Kim, MJ; Lee, S-Y; Hong, J
MLA Citation
Kwak, Seung-Hwa, et al. “Synthesis and evaluation of cyclopentane-based muraymycin analogs targeting MraY.Eur J Med Chem, vol. 215, Apr. 2021, p. 113272. Pubmed, doi:10.1016/j.ejmech.2021.113272.
URI
https://scholars.duke.edu/individual/pub1474795
PMID
33607457
Source
pubmed
Published In
Eur J Med Chem
Volume
215
Published Date
Start Page
113272
DOI
10.1016/j.ejmech.2021.113272

REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.

REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis. Rather, it increases hallmarks of senescence such as senescence-associated β-galactosidase, increased p21 expression, micronuclei formation, reduced Lamin B1, and increased expression of the immune regulators IL6 and IL8 followed by cell death. Moreover, although p-γ-H2AX foci formation was elevated and ATR expression was low in single agent cisplatin-treated cells, the opposite was true in cells treated with cisplatin/JH-RE-06. These observations suggest that targeting REV1 with JH-RE-06 profoundly affects the nature of the persistent genomic damage after cisplatin treatment and also the resulting physiological responses. These data highlight the potential of REV1/POLζ inhibitors to alter the biological response to DNA-damaging chemotherapy and enhance the efficacy of chemotherapy.
Authors
Chatterjee, N; Whitman, MA; Harris, CA; Min, SM; Jonas, O; Lien, EC; Luengo, A; Vander Heiden, MG; Hong, J; Zhou, P; Hemann, MT; Walker, GC
MLA Citation
Chatterjee, Nimrat, et al. “REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.Proc Natl Acad Sci U S A, vol. 117, no. 46, Nov. 2020, pp. 28918–21. Pubmed, doi:10.1073/pnas.2016064117.
URI
https://scholars.duke.edu/individual/pub1464140
PMID
33168727
Source
pubmed
Published In
Proc Natl Acad Sci U S A
Volume
117
Published Date
Start Page
28918
End Page
28921
DOI
10.1073/pnas.2016064117

Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors.

The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel antibiotics against multidrug-resistant Gram-negative pathogens. Recently, we reported the crystal structure of Klebsiella pneumoniae LpxH in complex with 1 (AZ1), a sulfonyl piperazine LpxH inhibitor. The analysis of the LpxH-AZ1 co-crystal structure and ligand dynamics led to the design of 2 (JH-LPH-28) and 3 (JH-LPH-33) with enhanced LpxH inhibition. In order to harness our recent findings, we prepared and evaluated a series of sulfonyl piperazine analogs with modifications in the phenyl and N-acetyl groups of 3. Herein, we describe the synthesis and structure-activity relationship of sulfonyl piperazine LpxH inhibitors. We also report the structural analysis of an extended N-acyl chain analog 27b (JH-LPH-41) in complex with K. pneumoniae LpxH, revealing that 27b reaches an untapped polar pocket near the di-manganese cluster in the active site of K. pneumoniae LpxH. We expect that our findings will provide designing principles for new LpxH inhibitors and establish important frameworks for the future development of antibiotics against multidrug-resistant Gram-negative pathogens.
Authors
Kwak, S-H; Cochrane, CS; Ennis, AF; Lim, WY; Webster, CG; Cho, J; Fenton, BA; Zhou, P; Hong, J
MLA Citation
Kwak, Seung-Hwa, et al. “Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors.Bioorg Chem, vol. 102, Sept. 2020, p. 104055. Pubmed, doi:10.1016/j.bioorg.2020.104055.
URI
https://scholars.duke.edu/individual/pub1452342
PMID
32663666
Source
pubmed
Published In
Bioorg Chem
Volume
102
Published Date
Start Page
104055
DOI
10.1016/j.bioorg.2020.104055