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

Director of Undergraduate Studies in 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

Publications:

Evaluation of Manassantin A Tetrahydrofuran Core Region Analogues and Cooperative Therapeutic Effects with EGFR Inhibition.

Tumors adapt to hypoxia by regulating angiogenesis, metastatic potential, and metabolism. These adaptations mediated by hypoxia-inducible factor 1 (HIF-1) make tumors more aggressive and resistant to chemotherapy and radiation. Therefore, HIF-1 is a validated therapeutic target for cancer. In order to develop new HIF-1 inhibitors for cancer chemotherapy by harnessing the potential of the natural product manassantin A, we synthesized and evaluated manassantin A analogues with modifications in the tetrahydrofuran core region of manassantin A. Our structure-activity relationship study indicated that the α,α'-trans-configuration of the central ring of manassantin A is critical to HIF-1 inhibition. We also demonstrated that a combination of manassantin A with an epidermal growth factor receptor inhibitor shows cooperative antitumor activity (∼80% inhibition for combination vs ∼30% inhibition for monotherapy). Our findings will provide important frameworks for the future therapeutic development of manassantin A-derived chemotherapeutic agents.
Authors
Kwak, S-H; Stephenson, TN; Lee, H-E; Ge, Y; Lee, H; Min, SM; Kim, JH; Kwon, D-Y; Lee, YM; Hong, J
MLA Citation
Kwak, Seung-Hwa, et al. “Evaluation of Manassantin A Tetrahydrofuran Core Region Analogues and Cooperative Therapeutic Effects with EGFR Inhibition.Journal of Medicinal Chemistry, vol. 63, no. 13, July 2020, pp. 6821–33. Epmc, doi:10.1021/acs.jmedchem.0c00151.
URI
https://scholars.duke.edu/individual/pub1448338
PMID
32579356
Source
epmc
Published In
Journal of Medicinal Chemistry
Volume
63
Published Date
Start Page
6821
End Page
6833
DOI
10.1021/acs.jmedchem.0c00151

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, June 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

A Stereoselective Formal Synthesis of Quinolizidine (–)-217A

© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim The stereoselective formal synthesis of quinolizidine alkaloid (–)-217A was achieved by utilizing a combination of the dithiane coupling reaction and the organocatalytic aza-conjugate addition reaction promoted by the gem-disubstituent effect to provide the functionalized 2,6-cis-piperidine ring system in a stereoselective manner.
Authors
Choi, H; Hong, J; Lee, K
MLA Citation
Choi, H., et al. “A Stereoselective Formal Synthesis of Quinolizidine (–)-217A.” European Journal of Organic Chemistry, vol. 2020, no. 6, Feb. 2020, pp. 689–92. Scopus, doi:10.1002/ejoc.201901680.
URI
https://scholars.duke.edu/individual/pub1431150
Source
scopus
Published In
European Journal of Organic Chemistry
Volume
2020
Published Date
Start Page
689
End Page
692
DOI
10.1002/ejoc.201901680

Resveratrol Protects Against Hydroquinone-Induced Oxidative Threat in Retinal Pigment Epithelial Cells.

Purpose: Oxidative stress in retinal pigment epithelial (RPE) cells is associated with age-related macular degeneration (AMD). Resveratrol exerts a range of protective biologic effects, but its mechanism(s) are not well understood. The aim of this study was to investigate how resveratrol could affect biologic pathways in oxidatively stressed RPE cells. Methods: Cultured human RPE cells were treated with hydroquinone (HQ) in the presence or absence of resveratrol. Cell viability was determined with WST-1 reagent and trypan blue exclusion. Mitochondrial function was measured with the XFe24 Extracellular Flux Analyzer. Expression of heme oxygenase-1 (HO-1) and glutamate cysteine ligase catalytic subunit was evaluated by qPCR. Endoplasmic reticulum stress protein expression was measured by Western blot. Potential reactions between HQ and resveratrol were investigated using high-performance liquid chromatography mass spectrometry with resveratrol and additional oxidants for comparison. Results: RPE cells treated with the combination of resveratrol and HQ had significantly increased cell viability and improved mitochondrial function when compared with HQ-treated cells alone. Resveratrol in combination with HQ significantly upregulated HO-1 mRNA expression above that of HQ-treated cells alone. Resveratrol in combination with HQ upregulated C/EBP homologous protein and spliced X-box binding protein 1. Additionally, new compounds were formed from resveratrol and HQ coincubation. Conclusions: Resveratrol can ameliorate HQ-induced toxicity in RPE cells through improved mitochondrial bioenergetics, upregulated antioxidant genes, stimulated unfolded protein response, and direct oxidant interaction. This study provides insight into pathways through which resveratrol can protect RPE cells from oxidative damage, a factor thought to contribute to AMD pathogenesis.
Authors
Neal, SE; Buehne, KL; Besley, NA; Yang, P; Silinski, P; Hong, J; Ryde, IT; Meyer, JN; Jaffe, GJ
MLA Citation
Neal, Samantha E., et al. “Resveratrol Protects Against Hydroquinone-Induced Oxidative Threat in Retinal Pigment Epithelial Cells.Invest Ophthalmol Vis Sci, vol. 61, no. 4, Apr. 2020, p. 32. Pubmed, doi:10.1167/iovs.61.4.32.
URI
https://scholars.duke.edu/individual/pub1441824
PMID
32334435
Source
pubmed
Published In
Investigative Opthalmology & Visual Science
Volume
61
Published Date
Start Page
32
DOI
10.1167/iovs.61.4.32

Length Specificity and Polymerization Mechanism of (1,3)-β-d-Glucan Synthase in Fungal Cell Wall Biosynthesis.

(1,3)-β-d-Glucan synthase (GS) catalyzes formation of the linear (1,3)-β-d-glucan in the fungal cell wall and is a target of clinically approved antifungal antibiotics. The catalytic subunit of GS, FKS protein, does not exhibit significant sequence homology to other glycosyltransferases, and thus, significant ambiguity about its catalytic mechanism remains. One of the major technical barriers in studying GS is the absence of activity assay methods that allow characterization of the lengths and amounts of (1,3)-β-d-glucan due to its poor solubility in water and organic solvents. Here, we report a successful development of a novel GS activity assay based on size-exclusion chromatography coupled with pulsed amperometric detection and radiation counting (SEC-PAD-RC), which allows for the simultaneous characterization of the amount and length of the polymer product. The assay revealed that the purified yeast GS produces glucan with a length of 6550 ± 760 mer, consistent with the reported degree of polymerization of (1,3)-β-d-glucan isolated from intact cells. Pre-steady state kinetic analysis revealed a highly efficient but rate-determining chain elongation rate of 51.5 ± 9.8 s-1, which represents the first observation of chain elongation by a nucleotide-sugar-dependent polysaccharide synthase. Coupling the SEC-PAD-RC method with substrate analogue mechanistic probes provided the first unambiguous evidence that GS catalyzes non-reducing end polymerization. On the basis of these observations, we propose a detailed model for the catalytic mechanism of GS. The approaches described here can be used to determine the mechanism of catalysis of other polysaccharide synthases.
Authors
Chhetri, A; Loksztejn, A; Nguyen, H; Pianalto, KM; Kim, MJ; Hong, J; Alspaugh, JA; Yokoyama, K
MLA Citation
Chhetri, Abhishek, et al. “Length Specificity and Polymerization Mechanism of (1,3)-β-d-Glucan Synthase in Fungal Cell Wall Biosynthesis.Biochemistry, vol. 59, no. 5, Feb. 2020, pp. 682–93. Pubmed, doi:10.1021/acs.biochem.9b00896.
URI
https://scholars.duke.edu/individual/pub1426925
PMID
31899625
Source
pubmed
Published In
Biochemistry
Volume
59
Published Date
Start Page
682
End Page
693
DOI
10.1021/acs.biochem.9b00896