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 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:

Structure-Guided Synthesis of FK506 and FK520 Analogs with Increased Selectivity Exhibit In Vivo Therapeutic Efficacy against Cryptococcus.

Calcineurin is an essential virulence factor that is conserved across human fungal pathogens, including Cryptococcus neoformans, Aspergillus fumigatus, and Candida albicans. Although an excellent target for antifungal drug development, the serine-threonine phosphatase activity of calcineurin is conserved in mammals, and inhibition of this activity results in immunosuppression. FK506 (tacrolimus) is a naturally produced macrocyclic compound that inhibits calcineurin by binding to the immunophilin FKBP12. Previously, our fungal calcineurin-FK506-FKBP12 structure-based approaches identified a nonconserved region of FKBP12 that can be exploited for fungus-specific targeting. These studies led to the design of an FK506 analog, APX879, modified at the C-22 position, which was less immunosuppressive yet maintained antifungal activity. We now report high-resolution protein crystal structures of fungal FKBP12 and a human truncated calcineurin-FKBP12 bound to a natural FK506 analog, FK520 (ascomycin). Based on information from these structures and the success of APX879, we synthesized and screened a novel panel of C-22-modified compounds derived from both FK506 and FK520. One compound, JH-FK-05, demonstrates broad-spectrum antifungal activity in vitro and is nonimmunosuppressive in vivo. In murine models of pulmonary and disseminated C. neoformans infection, JH-FK-05 treatment significantly reduced fungal burden and extended animal survival alone and in combination with fluconazole. Furthermore, molecular dynamic simulations performed with JH-FK-05 binding to fungal and human FKBP12 identified additional residues outside the C-22 and C-21 positions that could be modified to generate novel FK506 analogs with improved antifungal activity. IMPORTANCE Due to rising rates of antifungal drug resistance and a limited armamentarium of antifungal treatments, there is a paramount need for novel antifungal drugs to treat systemic fungal infections. Calcineurin has been established as an essential and conserved virulence factor in several fungi, making it an attractive antifungal target. However, due to the immunosuppressive action of calcineurin inhibitors, they have not been successfully utilized clinically for antifungal treatment in humans. Recent availability of crystal structures of fungal calcineurin-bound inhibitor complexes has enabled the structure-guided design of FK506 analogs and led to a breakthrough in the development of a compound with increased fungal specificity. The development of a calcineurin inhibitor with reduced immunosuppressive activity and maintained therapeutic antifungal activity would add a significant tool to the treatment options for these invasive fungal infections with exceedingly high rates of mortality.
Authors
Hoy, MJ; Park, E; Lee, H; Lim, WY; Cole, DC; DeBouver, ND; Bobay, BG; Pierce, PG; Fox, D; Ciofani, M; Juvvadi, PR; Steinbach, W; Hong, J; Heitman, J
MLA Citation
Hoy, Michael J., et al. “Structure-Guided Synthesis of FK506 and FK520 Analogs with Increased Selectivity Exhibit In Vivo Therapeutic Efficacy against Cryptococcus.Mbio, vol. 13, no. 3, June 2022, p. e0104922. Pubmed, doi:10.1128/mbio.01049-22.
URI
https://scholars.duke.edu/individual/pub1521547
PMID
35604094
Source
pubmed
Published In
Mbio
Volume
13
Published Date
Start Page
e0104922
DOI
10.1128/mbio.01049-22

SARS-CoV-2 hijacks host cell genome instability pathways.

The repertoire of coronavirus disease 2019 (COVID-19)-mediated adverse health outcomes has continued to expand in infected patients, including the susceptibility to developing long-COVID; however, the molecular underpinnings at the cellular level are poorly defined. In this study, we report that SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection triggers host cell genome instability by modulating the expression of molecules of DNA repair and mutagenic translesion synthesis. Further, SARS-CoV-2 infection causes genetic alterations, such as increased mutagenesis, telomere dysregulation, and elevated microsatellite instability (MSI). The MSI phenotype was coupled to reduced MLH1, MSH6, and MSH2 in infected cells. Strikingly, pre-treatment of cells with the REV1-targeting translesion DNA synthesis inhibitor, JH-RE-06, suppresses SARS-CoV-2 proliferation and dramatically represses the SARS-CoV-2-dependent genome instability. Mechanistically, JH-RE-06 treatment induces autophagy, which we hypothesize limits SARS-CoV-2 proliferation and, therefore, the hijacking of host-cell genome instability pathways. These results have implications for understanding the pathobiological consequences of COVID-19.
Authors
Victor, J; Jordan, T; Lamkin, E; Ikeh, K; March, A; Frere, J; Crompton, A; Allen, L; Fanning, J; Lim, WY; Muoio, D; Fouquerel, E; Martindale, R; Dewitt, J; deLance, N; Taatjes, D; Dragon, J; Holcombe, R; Greenblatt, M; Kaminsky, D; Hong, J; Zhou, P; tenOever, B; Chatterjee, N
MLA Citation
Victor, Joshua, et al. “SARS-CoV-2 hijacks host cell genome instability pathways.Res Sq, Apr. 2022. Pubmed, doi:10.21203/rs.3.rs-1556634/v1.
URI
https://scholars.duke.edu/individual/pub1517880
PMID
35441168
Source
pubmed
Published In
Res Sq
Published Date
DOI
10.21203/rs.3.rs-1556634/v1

REV1 Inhibition Enhances Radioresistance and Autophagy.

Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1's important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens.
Authors
Ikeh, KE; Lamkin, EN; Crompton, A; Deutsch, J; Fisher, KJ; Gray, M; Argyle, DJ; Lim, WY; Korzhnev, DM; Hadden, MK; Hong, J; Zhou, P; Chatterjee, N
MLA Citation
Ikeh, Kanayo E., et al. “REV1 Inhibition Enhances Radioresistance and Autophagy.Cancers (Basel), vol. 13, no. 21, Oct. 2021. Pubmed, doi:10.3390/cancers13215290.
URI
https://scholars.duke.edu/individual/pub1499235
PMID
34771454
Source
pubmed
Published In
Cancers
Volume
13
Published Date
DOI
10.3390/cancers13215290

REV1 Inhibition Enhances Radioresistance and Autophagy

<jats:p>Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1&amp;rsquo;s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. Collectively, we report a possible role of REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with significant bearing on cancer treatment regimens.</jats:p>
Authors
Ikeh, K; Lamkin, E; Crompton, A; Deutsch, J; Fisher, K; Gray, ME; Argyle, D; Lim, W; Korzhnev, D; Hadden, MK; Hong, J; Zhou, P; Chatterjee, N
MLA Citation
Ikeh, Kanayo, et al. REV1 Inhibition Enhances Radioresistance and Autophagy. Crossref, doi:10.20944/preprints202109.0202.v1.
URI
https://scholars.duke.edu/individual/pub1497077
Source
crossref
DOI
10.20944/preprints202109.0202.v1

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, Caroline G., et al. “Synthetic efforts toward the bicyclo[3.2.1]octane fragment of rhodojaponin III.Tetrahedron Letters, vol. 71, May 2021, p. 153055. Epmc, doi:10.1016/j.tetlet.2021.153055.
URI
https://scholars.duke.edu/individual/pub1480734
PMID
34054153
Source
epmc
Published In
Tetrahedron Letters
Volume
71
Published Date
Start Page
153055
DOI
10.1016/j.tetlet.2021.153055