Robert J. Geraghty, PhD

Anti-Viral Drug Discovery (1) Identify small molecule inhibitors of viral endonucleases. We study endonucleases from many viruses including human cytomegalovirus, coronaviruses, and influenza A virus. We investigate the structure and function of viral endonucleases to understand how they contribute to viral replication and to guide drug discovery efforts. We also develop assays for enzyme function and to screen rationally designed or random compounds to identify inhibitors. (2)  Identify small molecule inhibitors of flavivirus and coronavirus replication.  We are interested in rational design and random screening to identify compounds capable of blocking flavivirus or coronavirus replication. Currently, we are investigating dengue and Zika viruses as well as SARS-CoV-2 and our focus is on small molecules to block viral RNA synthesis and genome replication.

• Jung, E., Majima, R., Edwards, T.C., Soto-Acosta, R., Geraghty, R.J., Wang, Z., (2022). 8-Hydroxy-1,6-naphthyridine-7-carboxamides inhibit human cytomegalovirus pUL89 endonuclease with significant antiviral activities. ChemMedChem.https://doi.org/10.1002/cmdc.202200334.

• Jung, E., Soto-Acosta, R., Xie, J., Wilson, D.J., Dreis, C.D., Majima, R., Edwards, T.C., Geraghty, R.J., Chen, L, (2022).Bi-substate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase. Med Chem Letters13(9):1477-1484. https://doi.org/10.1021/acsmedchemlett.2c00265.

• He, T*., Edwards, T.C.*, Xie, J., Aihara, H., Geraghty, R.J., Wang, Z., (2022) 4,5-Dihydroxypyrimidine methyl carboxylates, carboxylic acids, and carboxamides as inhibitors of human cytomegalovirus pUL89 endonuclease. J Med Chem 65(7):5830-5849. https://doi.org/10.1021/acs.jmedchem.2c00203.

• Senaweera, S., Edwards, T.C., Kankanala, J.K., Wang, Y., Sahani, R.L., Xie, J., Geraghty, R.J., Wang, Z. (2022) Discovery of N-benzyl Hydroxypyridone carboxamides as a Novel and Potent Antiviral Chemotype Against Human Cytomegalovirus (HCMV). Acta Pharmaceutica Sinica B 12(4):1671-1684. https://doi.org/10.1016/j.apsb.2021.08.019.

• Soto-Acosta R., Edwards T.C., Dreis C.D., Krishna V.D., Cheeran MC., Qiu L., Xie J., Bonnac L.F.*, Geraghty R.J.*, (2021) Enhancing the Antiviral Potency of Nucleobases for Potential Broad-Spectrum Antiviral Therapies. Viruses13(12):2508. https://doi.org/10.3390/v13122508.

• Soto-Acosta, R., Jung, E., Qiu, L., Wilson, D.J., Geraghty, R.J.*, Chen, L.*, (2021) 4,7-Disubstituted 7H-pyrrolo[2,3-d]pyrimidines and Their Analogs as Antiviral Agents Against Zika Virus. Molecules 26(13):3779 doi: 10.3390/molecules26133779.

• Wang, L., Edwards, T.C., Sahani R.L., Xie, J., Aihara, H., Geraghty, R.J., Wang, Z, (2021) Metal Binding 6-arylthio-3-hydroxypyrimidine-2,4-diones Inhibited Human Cytomegalovirus by Targeting the pUL89 Endonuclease of the Terminase Complex. European Journal Medicinal Chemistry 222:113640 doi: 10.1016/j.ejmech.2021.113640.

• Geraghty, R.J., Aliota, M.T., Bonnac, L.F., (2021) Broad-Spectrum Antiviral Strategies and Nucleoside Analogues. Viruses 13:667 https://doi.org/10.3390/v13040667.
• Seneviratne U., Wickramaratne S., Kotandeniya D., Groehler A., Geraghty, R.J., Dreis C., Pujari, S.S., Tretyakova, N.Y., (2021) Synthesis and Biological Evaluation of Pyrrolidine-Functionalized Nucleoside Analogs. Medicinal Chemistry Research 30:483–499 https://doi.org/10.1007/s00044-021-02700-1.
• Wang, Y., Soto-Acosta, R., Ding, R., Chen, L.*, Geraghty, R.J.*, (2021) Anti-HCMV Activity by an Irreversible p97 Inhibitor LC-1310. Medicinal Chemistry Research 30:440–448 https://doi.org/10.1007/s00044-020-02679-1.
• Wu, J., Zhang, J., Soto-Acosta, R., Mao, L., Lian, J., Chen, K., Pillon, G., Zhang, G., Geraghty, R.J., Zheng, S., (2020) One-Pot Synthesis of 1-Hydroxyacridones from para-Quinols and ortho-Methoxycarbonylaryl Isocyanates. The Journal of Organic Chemistry 85(6):4515-4524.
• Bonnac, L.F., Dreis, C.D., Geraghty, R.J., (2020) Structure Activity Relationship, 6-Modified Purine Riboside Analogues to Activate hSTING, Stimulator of Interferon Genes. Bioorganic & Medicinal Chemistry Letters 30(2): 126819.
• Wang Y., and Geraghty R.J., (2019) FRET-based assay using a three-way junction DNA substrate to identify inhibitors of human cytomegalovirus pUL89 endonuclease activity. Eur. J. Pharm. Sci. 2019; 127:29-37.
• Kankanala J., Wang Y., Geraghty R.J., and Wang Z., (2018) Hydroxypyridonecarboxylic Acids as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease. ChemMedChem 13(16):1658-1663.
• Wang, Y., Tang, J., Wang, Z., and Geraghty, R.J., (2018) Metal-chelating 3-hydroxypyrimidine-2,4-diones inhibit human cytomegalovirus pUL89 endonuclease activity and virus replication. Antiviral Res. 152:10-17.
• Qiu, L., Patterson, S.E., Bonnac, L.F.*,and Geraghty, R.J.*, (2018) Nucleobases and corresponding nucleosides display potent antiviral activities against dengue virus, possibly through viral lethal mutagenesis. PLoS Neglected Trop. Dis. 12(4): e30006421. *Denotes co-contributing authors
• Zhou, W., Wang, Y., Xie, J. and Geraghty, R.J., (2017) A Fluorescence-Based High-Throughput Assay to Identify Inhibitors of Tyrosylprotein Sulfotransferase Activity. Biochemistry and Biophysics Research Communications 482:1207-1212.
• Wang, Y., Mao, L., Kankanala, J., Wang, Z.,and Geraghty, R. J., (2017) Inhibition of Human Cytomegalovirus pUL89 Terminase Subunit Blocks Virus Replication and Genome Cleavage. Journal of Virology 91(3): e02152-16.
• Ai, T.; Xu, Y.; Qiu, L.; Geraghty, R. J.; Chen, L. Hydroxamic acids block replication of hepatitis C virus. J. Med. Chem. 2015, 58, 785-800. PubMed PMID: 25490700.
• Vernekar, S. K.; Qiu, L.; Zhang, J.; Kankanala, J.; Li, H.; Geraghty, R. J.; Wang, Z. 5'-Silylated 3'-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus. J. Med. Chem. 2015, 58, 4016-4028. NIHMSID: NIHMS695073. PubMed PMID: 25909386 PMCID: PMC4465584.
• Ai, T.; Qiu, L.; Xie, J.; Geraghty, R. J.; Chen, L. Design and synthesis of an activity-based protein profiling probe derived from cinnamic hydroxamic acid. Bioorg. Med. Chem. 2016, 24, 686-692. PubMed PMID: 26753813.
• Zhou, W.; Duckworth, B. P.; Geraghty, R. J. Fluorescent peptide sensors for tyrosylprotein sulfotransferase activity. Anal. Biochem. 2014, 461, 1-6.
• Vernekar, S. K. V.; Qiu, L.; Zacharias, J.; Geraghty, R. J.; Wang, Z. Synthesis and antiviral evaluation of 4’-(1,2,3-triazol-1-yl)thymidines. Med. Chem. Commun. 2014, 5, 603-608.
• Zhou, W.; Chen, F.; Klyachkin, Y.; Sham, Y. Y.; Geraghty, R. J.; Mutations in the amino terminus of herpes simplex virus type 1 gL can reduce cell-cell fusion without affecting gH/gL trafficking. J. Virol. 2013, 88, 739-744.
• Wu, K.; Peng, G.; Wilken, M.; Geraghty, R. J.; Li, F. Mechanisms of host receptor adaptation by severe acute respiratory syndrome coronavirus. J. Biol. Chem. 2012, 287, 8904-8911.
• Chen, Y.-L.; Zacharias, J.; Vince, R.; Geraghty, R. J.; Wang, Z. C-6 Aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus. Bioorg. Med. Chem. 2012, 20, 4790-4800.
• Chen, Y.-L.; Tang, J.; Kesler, M. J.; Sham, Y. Y.; Vince, R.; Geraghty, R. J.; Wang, Z. The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus. Bioorg. Med. Chem. 2012, 20, 467-479.
• Wu, K.; Chen, L.; Peng, G.; Zhou, W.; Pennell, C. A.; Mansky, L. M.; Geraghty, R. J.; Li, F. A virus-binding hot spot on human angiotensin-converting enzyme 2 is critical for binding of two different coronaviruses. J. Virol. 2011, 85, 5331-5337.
• Klyachkin, Y. M.; Geraghty, R. J. Mutagenic analysis of herpes simplex virus type 1 glycoprotein L reveals the importance of an arginine-rich region for function. Virology 2008, 374, 23-32.
• Subramanian, R. P.; Geraghty, R. J. Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 2903-2908.
• Klyachkin, Y. M.; Stoops, K. D.; Geraghty, R. J. Herpes simplex virus type 1 glycoprotein L mutants that fail to promote trafficking of glycoprotein H and fail to function in fusion can induce binding of glycoprotein L-dependent anti-glycoprotein H antibodies. J. Gen. Virol. 2006, 87, 759-767.
• Even, D. L.; Henley, A. M.; Geraghty, R. J. The requirements for herpes simplex virus type 1 cell-cell spread via nectin-1 parallel those for virus entry. Virus Res. 2006, 119, 195-207.
• Subramanian, R. P.; Dunn, J. E.; Geraghty, R. J. The nectin-1? transmembrane domain, but not the cytoplasmic tail, influences cell fusion induced by HSV-1 glycoproteins. Virology 2005, 339, 176-191.
• Jones, N. A.; Geraghty, R. J. Fusion activity of lipid-anchored envelope glycoproteins of herpes simplex virus type 1. Virology 2004, 324, 213-228.
• Terry-Allison, T.; Montgomery, R. I.; Warner, M. S.; Geraghty, R. J.; Spear, P. G. Contributions of gD receptors and glycosaminoglycan sulfation to cell fusion mediated by herpes simplex virus 1. Virus Res. 2001, 74, 39-45.
• Geraghty, R. J.; Fridberg, A.; Krummenacher, C.; Cohen, G. H.; Eisenberg, R. J.; Spear, P. G. Use of chimeric nectin-1(HveC)-related receptors to demonstrate that ability to bind alphaherpesvirus gD is not necessarily sufficient for viral entry. Virology 2001, 285, 366-375.
• Baury, B.; Geraghty, R. J.; Masson, D.; Lustenberger, P.; Spear, P. G.; Denis, M. G. Organization of the rat Tage4 gene and herpesvirus entry activity of the encoded protein. Gene 2001, 265, 185-194.
• Geraghty, R. J.; Jogger, C. R.; Spear, P. G. Cellular expression of alphaherpesvirus gD interferes with entry of homologous and heterologous alphaherpesviruses by blocking access to a shared gD receptor. Virology 2000, 268, 147-158.
• Krummenacher, C.; Rux, A. H.; Whitbeck, J. C.; Ponce-De-Leon, M.; Lou, H.; Baribaud, I.; Hou, W.; Zou, C.; Geraghty, R. J.; Spear, P. G.; Eisenberg, R. J.; Cohen, G. H. The first immunoglobulin-like domain of HveC is sufficient to bind herpes simplex virus gD with full affinity, while the third domain is involved in oligomerization of HveC. J. Virol. 1999, 73, 8127-8137.
• Warner, M. S.; Geraghty, R. J.; Martinez, W. M.; Montgomery, R. I.; Whitbeck, C.; Xu, R.; Eisenberg, R. J.; Cohen, G. H.; Spear, P. G. A cell surface protein with herpesvirus entry activity (HveB) confers susceptibility to infection by mutants of herpes simplex virus type 1, herpes simplex virus type 2, and pseudorabies virus. Virology 1998, 246, 179-189.
• Krummenacher, C.; Nicola, A. V.; Whitbeck, J. C.; Lou, H.; Hou, W.; Lambris, J. D.; Geraghty, R. J.; Spear, P. G.; Cohen, G. H.; Eisenberg, R. J. Herpes simplex virus glycoprotein D can bind to poliovirus receptor-related protein 1 or herpesvirus entry mediator, two structurally unrelated mediators of virus entry. J. Virol. 1998, 72, 7064-7074.
• Geraghty, R. J.; Krummenacher, C.; Cohen, G. H.; Eisenberg, R. J.; Spear, P. G. Entry of alphaherpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor. Science 1998, 280, 1618-1620.
• Schwartz, M. D.; Geraghty, R. J.; Panganiban, A. T. HIV-1 particle release mediated by Vpu is distinct from that mediated by p6. Virology 1996, 224, 302-309.
• Geraghty, R. J.; Talbot, K. J.; Callahan, M.; Harper, W.; Panganiban, A. T. Cell type-dependence for Vpu function. J. Med. Primatol. 1994, 23, 146-150.
• Geraghty, R. J.; Panganiban, A. T. Human immunodeficiency virus type 1 Vpu has a CD4- and an envelope glycoprotein-independent function. J. Virol. 1993, 67, 4190-4194.

Research Funding Grants

Completed:

7/1/96 – 6/30/99: F32 AI09471.Individual National Research Support Award. Department of Health and Human Services, National Institute of Health. Protein Interactions In Herpesvirus Cell Fusion.

01/01/02 – 12/31/02 American Cancer Society
Institutional Research Grant
Cellular Factors In Cell-To-Cell Spread Of Herpesviruses, Principal Investigator, $20,000 direct costs.
Role: PI

9/30/02 – 2/28/08
R01 AI051476 NIH/NIAID
Spread Of HSV-1 Mediated By The gD Receptor Nectin-1. National Institute of Health. National Institute of Allergy and Infectious Diseases.
Role: PI

5/15/09 – 5/14/12
RO3 AI078079 NIH/NIAID
Membrane fusion during HSV-1 entry.
Role: PI

6/1/10 – 5/31/15
R01 AI089728 NIH/NIAID
Receptor recognition mechanisms of coronaviruses.
Role: Co-Investigator (Dr. Fang Li Principal Investigator)

7/1/12 – 6/30/14
Center for Drug Design Research Development and Seed Grant
Identification Of Inhibitors Of HCMV UL89 Terminase And HCMV Replication
Role: PI

7/1/14 – 6/30/18
Center for Drug Design Research Development and Seed Grant
Viral Endonucleases.
Role: PI

9/1/16 – 8/31/18
University of Minnesota AHC Faculty Research Development Grant Program
Development of biological and structural approaches to Zika virus drug discovery
Role: PI

4/01/2020 – 3/31/2022
R21 AI151427-01            NIH/NIAID
Optimizing Zika NS5 Methyltransferase Inhibitors
Role: Co-I (Liqiang Chen PI)

Current:

1/25/19-12/31/24
R01 AI136982-01 NIH/NIAID
Discovery and development of novel anti-HCMV agents targeting the UL89 terminase protein
Role: Co-PI (Zhengqiang Wang Co-PI)

07/01/2022 – 06/30/2024
R21 AI166065             NIH/NIAID
Bi-substrate inhibitors of SARS-CoV-2 Nsp14 methyltransferase
Role: Co-I (Liqiang Chen PI)
 

Patents

• Wang, Z.; Geraghty, R. J.; Vince, R.; Tang, J. (University of Minnesota, USA). N-Hydroxypyrimidine-2,4-diones as inhibitors of HIV and HCV and their preparation. Application: WO 20111005.; SciFinder Scholar 2012:533369.
• Spear, P.G., Geraghty, R.J., Martinez, W.M., Montgomery, R.I., Warner, M.S., Cohen, G.H., Eisenberg, R.J., Whitbeck, C.J., and Krummenacher, C. Cellular Proteins Which Mediate Herpesvirus Entry, U.S. Patent # 6,641,818. 2000.
• 2020. Bonnac, L.F. and Geraghty, R.J. Potentiation of Antiviral Nucleobases as RNA Virus Therapy. Provisional. International Patent Application Serial No.: PCT/US2020/041133.