Wang Group

Wang Group Research Projects

Wang Group Research Projects

Wang core expertise

Our research focuses primarily on the discovery and development of novel antiviral agents. We are committed to the full spectrum of drug discovery efforts combining lead generation, SAR design, organic synthesis, viral enzyme biochemical assays, cell culture antiviral assays and pharmacology.

Antiviral Target Validation

Antiviral Target Validation

Antiviral Target Validation

Capsid Targeting Antivirals

Anticancer Drug Discovery

Anticancer Drug Discovery

Other than antiviral projects, we are also working on tyrosyl DNA phosphodiesterase 1 (Tdp1) as a target for anti-cancer therapy. Tdp1 is a DNA repair enzyme that is associated with drug resistance of topoisomerase I (Top I) inhibitors (e.g. camptothecin). Inhibition of Tdp1 should potentiate the efficacy of Top I inhibitors. However, no potent Tdp1 inhibitor is known to date. Through collaboration with NCI we have identified multiple molecular scaffolds showing great promise in Tdp1 inhibition. SAR efforts are underway to optimize them as lead compounds.

Anticancer Drug Discovery

 

TDP2

Novel Nucleoside Chemotypes

Novel Nucleoside Chemotypes

Novel Nucleoside Chemotypes

Antiviral Drug Discovery

Antiviral Drug Discovery

Due to the lack of efficacious vaccine and the ability of the virus to establish latency, management of HIV / AIDS relies solely on uninterrupted combination chemotherapy termed as Highly Active Anti-Retroviral Therapy (HAART). The rapid selection of resistant viral strains under drug pressure, however, creates a major barrier to achieving sustained virological response (SVR) for successful HAART treatment. To counter resistance we are currently exploring three distinct strategies:

  1. Studying viral and cellular pathways that could be utilized as novel intervention targets; 
  2. Identifying novel chemotypes capable of inhibiting validated therapeutic targets, such as HIV integrase (IN) and reverse transcriptase (RT), by combining structure-based design and organic synthesis; 
  3. Developing novel inhibitors that could accommodate inhibitory activities against two important HIV enzymes, e.g. RT and IN.

Wang Antiviral Drug Discovery

HIV/HCV Co-Infection


The weakening of immune system by HIV allows various opportunistic infections, amongst which HCV co-infection represents a particularly challenging complication in HIV / AIDS chemotherapy as over 50% of AIDS mortality is caused by HCV-associated severe liver diseases. Current therapies for HIV and HCV appear to antagonize each other. Therefore, there is an urgent need to develop mutually compatible antivirals to deal with HIV / HCV co-infection. In this line, we are exploring a few chemotypes as dually active inhibitors against both HIV and HCV.

Influenza


Polymerase provides a major platform for chemotherapeutic intervention across the antiviral realm. However, in the case of influenza A, polymerase remains an underexplored target for inhibitor design. Using a strategy combining structure mining and clustering, we have created a small focused compound library consisting mainly of nucleoside compounds. These compounds are being assayed against a viral sub-genomic cell culture system. Other chemotypes likely targeting the endonuclease activity of polymerase are also being investigated.

Hepatitis B Virus (HBV)

HBV chronically infects 350 million people. Current HBV drugs all target reverse transcription and do not impact the covalently closed-circular DNA (cccDNA), the reservoir for viral persistence. Achieving HBV eradication and disease cure would require the elimination of cccDNA. One way to impact viral ccDNA would be to disrupt the assembly of capsid which is crucial to cccDNA maintenance. We are currently working on identifying small molecule capsid assembly effectors (CAEs) (grant support: NIAID 5R01AI121315). In addition, we are also exploring the impact of inhibiting cellular DNA repair enzyme TDP2 on the formation of viral cccDNA from relaxed circular DNA (RC-DNA). 
HBV

Current Group Members

Eunkyung Jung

Eunkyung 'Kelly' Jung, PhD
Postdoctoral Associate
ejung@umn.edu

 

Carlos Ribeiro

Carlos Ribeiro, PhD
Postdoctoral Associate
cribeiro@umn.edu

 

Sameera Senaweera 360x420
Sameera Senaweera, PhD
Postdoctoral Associate
ssenawee@umn.edu

 

Lei Wang

Lei Wang, PhD
Postdoctoral Associate
wang7275@umn.edu

Publications

  • Tang, J.; Do, H. T.; Huber, A. D.; Casey, M. C.; Wilson, D. J.; Kirby, K. A.; Sarafianos, S. G.; Wang, Z.* " Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: tolerance of a nonflexible linker " Eur. J. Med. Chem. 2019, accepted.
  • Ribeiro, C.; Kankanala, J.; Xie, J.; Williams, J.; Aihara, H.; Wang, Z.* " Triazolopyrimidine and triazolopyridine as inhibitor scaffolds of tyrosyl-DNA phosphodiesterase 2 (TDP2) " Bioorg. Med. Chem. Lett., 201929, 257-261.
  • Huber, A. D.; Pineda, D. L.; Liu, D.; Boschert, K. N.; Gres, A. T.; Wolf, J. J.; Coonrod, E. M.; Tang, J.; Laughlin, T. G.; Yang, Q.; Puray-Chavez, M. N.; Ji, J.; Singh, K.; Kirby, K. A.; Wang, Z.; Sarafianos, S. G., Novel hepatitis B virus capsid-targeting antiviral that aggregates core particles and inhibits nuclear entry of viral cores. ACS Infect. Dis. 2018. doi: 10.1021/acsinfecdis.8b00235
  • Tang, J.; Huber, A. D.; Pineda, D. L.; Boschert, K. N.; Kankanala, J.; Xie, J.; Sarafianos, S. G.; Wang, Z.* " 5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors  " Eur. J. Med. Chem. 2018164, 179-192.
  • Wang, L.; Tang, J.; Huber, A. D.; Casey, M. C.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Parniak, M. A.; Sarafianos, S. G.; Wang, Z.* "6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones as potent and selective inhibitors of HIV reverse transcriptase-associated RNase H" Eur. J. Med. Chem. 2018, 156, 680-691.
  • Wang, L.; Tang, J.; Huber, A. D.; Casey, M. C.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Xie, J.; Parniak, M. A.; Sarafianos, S. G.; Wang, Z.*" 6-Arylthio-3-hydroxypyrimidine-2,4-diones potently inhibited HIV reverse transcriptase-associated RNase H with antiviral activity" Eur.J. Med. Chem. 2018, 156, 652-665.
  • Kankanala, J.; Wang, Y.; Geraghty, B. J. Wang, Z. “Hydroxypyridonecarboxylic Acids as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease” ChemMedChem, 2018, DOI: https://doi.org/10.1002/cmdc.201800283.
  • Ribeiro, C.; Kankanala, J.; Shi, K.; Kurahashi, K.; Kiselev, E.; Ravji, A.; Pommier, Y.; Aihara, H.; Wang, Z.* "New fluorescence-based high-throughput screening assay for small molecule inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2)" Eur. J. Pharm. Sci. 2018,118, 67-79.
  • Bohl, T.; Leong, P.; Lee, J.; Lee, T.; Kankanala, J.; Shi, K.; Demir, O.; Kurahashi, K.; Amaro, R.; Wang, Z.; Aihara, H. "The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release" J. Biol. Chem. 2018, 293, 7969-7981.
  • Huber, A. D.; Liu, D.; Gres, A. T.; Puray-Chavez, M. N.; Tang, J.; Boschert, K. N.; Pineda, D. L.; Laughlin, T. G.; Yang, Q.; Ji, J.; Kirby, K. A.; Wang, Z.; Sarafianos, S. G.; "The heteroaryldihydropyrimidine Bay 38-7690 induces hepatitis B virus core protein aggregates associated with promyelocytic leukemia nuclear bodies in infected cells" mSphere 20183, e00131-18.
  • Wang, Y.; Tang, J.; Wang, Z.; Geraghty, R. J. "Metal-Chelating 3-Hydroxypyrimidine-2,4-diones Inhibit Human Cytomegalovirus pUL89 Endonuclease Activity and Virus Replication " Antiviral Res. 2018152, 10-17.
  • Kankanala, J.; Kirby, K. A.; Huber, A. D.; Casey, M. C.; Wilson, D. J.; Sarafianos, S. G.; Wang, Z.* "Design, Synthesis and Biological Evaluations of N-Hydroxy thienopyrimidine-2,4-diones as Inhibitors of HIV Reverse Transcriptase-Associated RNase H" Eur. J. Med. Chem. 2017, 141, 149-161.
  • Vernekar, S. K. V.; Tang, J.; Wu, B.; Huber, A. D.; Casey, M. C.; Myshakina, N.; Wilson, D. J.; Kankanala, J.; Kirby, K. A.; Parniak, M. P.; Sarafianos, S. G.; Wang, Z.* "Double-winged 3-Hydroxypyrimidine-2,4-diones: Potent and Selective Inhibition against HIV-1 RNase H with Significant Antiviral Activity" J. Med. Chem. 2017, 60, 5045-5056. Selected for the “Fighting HIV with Chemistry” virtual issue.
  • Kirby, K. A.; Myshakina, N. A.; Christen, M. T.; Chen, Y.-L.; Schmidt, H. A.; Huber, A. D.; Xi, Z.; Kim, S.; Rao, R. K.; Kramer, S. T.; Yang, Q.; Singh, K,; Parniak, M. A.; Wang, Z.; Ishima, R.; Sarafianos, S. G. “A 2-hydroxylisoquinoline-1,3-dione active site RNase H inhibitor binds in multiple modes to HIV-1 reverse transcriptase” Antimicrob. Agents Chemother. 2017, 61, e01351-17.
  • Tang, J.; Vernekar, S. K. V.; Chen, Y.-L.; Miller, L.; Huber, A. D.; Myshakina, N.; Sarafianos, S. G.; Parniak, M. P.; Wang, Z.* "Synthesis, Biological Evaluation and Molecular Modeling of 2-Hydroxyisoquinoline-1,3-dione Analogues as Inhibitors of HIV Reverse Transcriptase Associated Ribonulease H and Polymerase" Eur. J. Med. Chem. 2017, 133, 85-96.
  • Huber, A. D.; Michailidis, E.; Tang, J.; Puray-Chavez, M.; Boftsi, M.; Wolf, J.; Boschert, K.; Sheridan, M.; Leslie, M.; Kirby, K. A.; Singh, K.; Mitsuya, H.; Parniak, M. A.; Wang, Z.; Sarafianos, S. G. "3-hydroxypyrimidine-2,4-diones as novel hepatitis B virus antivirals targeting the viral ribonuclease H" Antimicrob. Agents Chemother. 2017, 61, e00245-17.
  • Tang, J.; Kirby, K. A.; Huber, A. D.; Casey, M. C.; Ji, J.; Wilson, D. J.; Sarafianos, S. G.; Wang, Z.* "6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an Inhibitor Scaffold of HIV Reverse Transcriptase: Impacts of the 3-OH on Inhibiting RNase H and Polymerase" Eur. J. Med. Chem. 2017, 128, 168-179.
  • Wang, Y.; Mao, L.; Kankanala, J.; Wang, Z.; Geraghty, R. J. "Inhibition of Human Cytomegalovirus pUL89 Terminase Subunit Blocks Virus Replication and Genome Cleavage " J. virol.  2016, 91, e02152-e02156.
  • Wu, B.; Tang, J.; Wilson, D. J.; Huber, A. D.; Casey, M. C.; Ji, J.; Kankanala, J.; Xie, J.; Sarafianos, S. G.; Wang, Z.* "3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides potently inhibit HIV-1 integrase and RNase H " J. Med. Chem. 2016, 59, 6136-6148.
  •  Kankanala, J.; Liu, F.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z.* "Design, Synthesis and Biological Evaluations of Hydroxypyridone Carboxylic Acids as Inhibitors of HIV Reverse Transcriptase-Associated RNase H " J. Med. Chem. 2016, 59, 5051-5062.
  •  Marchand, C.; Abdelmalak, M.; Fesen, K.; Kankanala, J.; Aihara, H.; Wang, Z.; Pommier, Y. “Deazaflavin inhibitors of tyrosyl phosphodiesterase 2 (TDP2) specific for the human enzyme and active against cellular TDP2” ACS Chem. Biol. 2016, 11, 1925-1933.
  •  Tang, J.; Liu, F.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Wu, B.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z.* "2-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations " J. Med. Chem. 2016, 59, 2648-2659.
  •  Kankanala, J.; Marchand, C.; Abdelmalak, M.; Aihara, H.; Pommier, Y.; Wang, Z.* "Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2)" J. Med. Chem. 2016, 59, 2734-2746.
  • Vernekar, S. K. V.; 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. (Abstract
  • Vernekar, S. K. V.; Liu, Z.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z.* “Design, Synthesis, Biochemical, and Antiviral Evaluations of C6 Benzyl and C6 Biarylmethyl Substituted 2-Hydroxylisoquinoline-1,3-diones: Dual Inhibition against HIV Reverse Transcriptase-Associated RNase H and Polymerase with Antiviral Activities” J. Med. Chem. 2015, 58, 651-664.
  • 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.
  •  Sirivolu, V. R.; Vernekar, S. K. V.; Ilina, T.; Myshakina, N. S.; Parniak, M. A.; Wang, Z.* "Clicking 3’-Azidothymidine into Novel Potent Inhibitors of Human Immunodeficiency Virus" J. Med. Chem. 2013, 56, 8765–8780. Abstract
  • Sirivolu, V. R; Vernekar, S. V; Marchand, C; Naumova, A; Chergui, A; Renaud, A; Stephen, A; Chen, F; Sham, Y. Y; Pommier, Y; Wang, Z.* “5-Arylidenethioxothiazolidinones as Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp1)” J. Med. Chem. 2012, 55, 8671-8684. Abstract
  • 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. Abstract
  • Kirby, K.; Marchand, B.; Ong, Y.; Adongwe, T.; Hachiya, A.; Michailidis, E.; Leslie, M.; Sietsema, D.; Fetterly, T.; Dorst, C.; Singh, K.; Wang, Z.; Parniak, M.; Sarafianos, S. "Structural and Inhibition Studies of the RNase H Function of Xenotropic Murine Leukemia Virus-Related Virus Reverse Transcriptase" Antimicrob. Agents Chemother. 2012, 56, 2048-2061. Abstract
  • 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. Abstract
  • Tang, J.; Maddali, K.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z.* “3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase” J. Med. Chem. 2011, 54, 2282-2292. Abstract
  • Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z.* “6-Benzoyl-3-hydroxypyrimidine-2,4-diones as Dual Inhibitors of HIV Reverse Transcriptase and Integrase” Bioorg. Med. Chem. Lett. 2011, 21, 2400-2402. Abstract
  • Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z.* “N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase” ACS Med. Chem. Lett. 2011, 2, 63-67. Abstract
  • Tang, J.; Maddali, K.; Pommier, Y.; Sham, Y. Y.; Wang, Z.* “Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited” Bioorg. Med. Chem. Lett.2010, 20, 3275-3279. Abstract
  • Wang, Z.*; Tang, J.; Salomon, E. C.; Dreis, C. D.; Vince, R. “Pharmacophore and Structure-Activity-Relationship on Integrase Inhibition within a Dual Inhibitor Scaffold of HIV Reverse Transcriptase and Integrase” Bioorg. Med. Chem. 2010, 18, 4202-4211. Abstract
  • Wang, Z.*; Vince, R. " Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: Introducing a diketoacid functionality into delavirdine" Bioorg. Med. Chem. 2008, 16, 3587-3595. Abstract
  • Wang, Z.*; Vince, R. “Synthesis of Pyrimidine and Quinolone Conjugates as a Scaffold for Dual Inhibitors of HIV Reverse Transcriptase and Integrase” Bioorg. Med. Chem. Lett. 2008, 18, 1293-1296. Abstract
  • Wang, Z.; Bennett, E. M; Wilson, D. J.; Salomon, C.; Vince, R. “Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase”. J. Med. Chem. 2007, 50, 3416. Abstract

Grants and Funding

Current

1) R01AI136982 (R01, NIAID / NIH) PIs: Robert Geraghty and Zhengqiang Wang                        
“Discovery and development of novel anti-HCMV agents targeting the UL89 terminase protein”.
The goal of this grant is to develop structurally novel direct-acting antivirals against HCMV targeting pUL89, a viral ATPase/endonuclease terminase complex component critically involved in viral genome packaging and virus assembly. 
Role: PI
Grant Period: 01/25/2019—01/24/2024

2) R01AI121315  (R01, NIAID / NIH)  PIs: Stefan Sarafianos and Zhengqiang Wang
“Taking aim at HBV eradication using novel NRTIs and capsid effectors”
The goal of this grant is to discover and characterize potent capsid effectors and study their antiviral effect in combination with NRTIs. 
Role: PI
Grant Period: 06/14/2016—06/13/2021

3) R01AI120860 (R01, NIAID / NIH)  PIs: Stefan Sarafianos and Zhengqiang Wang
“Structural studies of HIV Capsid with host factors and Capsid-targeting antivirals”. 
The goal of this grant is to characterize the structural determinants of HIV capsid (CA) core stability, to unravel structural interactions of CA with host factors and to discover CA-targeting antivirals.  
Role: PI
Grant Period: 06/15/2015-05/31/2020

Completed 

1) R01AI100890 (R01, NIAID / NIH) PIs: Stefan Sarafianos and Zhengqiang Wang
“Novel Antivirals Targeting the RNase H Activity of HIV Reverse Transcriptase”. 
The goal of this grant is to identify and optimize selective inhibitors of HIV RNase H and study detailed biochemistry of different modes of RNase H activities as well as inhibitor binding sites, and eventually validate RNase H as an antiviral target for HIV chemotherapy. 
Role: PI
Grant Period: 07/01/2012—06/30/2018

2) FDR#23. University of Minnesota AHC Faculty Research Development Grant
“Structure-Based Discovery of Tyrosyl DNA Phosphodiesterase 2 (TDP2) Inhibitors”
The goal of this grant is to identify inhibitor types and elucidate the mechanism of inhibition of TDP2 through a structure-based approach. 
Role: PI
Grant Period: 07/01/2014—06/30/2016

3) Research Development and Seed Grant, Center for Drug Design, University of Minnesota 
“3’ and 4’-Triazoyl Thymidines as Chemotypes for Antiviral Discovery” 
The goal of this project was to validate and enrich 3’ and 4’-triazoyl thymidine scaffolds as viable chemotypes for antiviral discovery  
Role: PI
Grant Period: 07/01/2012—06/30/2014

4) Research Development and Seed Grant, Center for Drug Design, University of Minnesota 
“Fragment Based Library Synthesis toward Small Molecule Inhibitors”” 
The goal of this grant is to curate and synthesize libraries of fragments and combined fragments for the discovery of inhibitors of various proteins 
Role: PI
Grant Period: 07/01/2014—06/30/2016

Group Alumni

Postdoctoral Associates

Yue-Lei Chen, PhD (02/2009-10/2010)
Current: Research Scientist at Shanghai Institute of Medica Meteria, Chinese Academy of Sciences, China

Venkata Ramana Sirivolu, PhD (2008-2011)
Current: Senior Research Scientist (Drug Discovery) at Jubilant Biosys, India

Zheng Liu, PhD (2012-2013)
Current: Professor, Department of Chemistry, Central China Normal University

Feng Liu, PhD (2012-2013)
Current: Research Scientist at AAT Bioquest

Bulan Wu, PhD (01/2014-06/2015)
Current: Assistant Professor, University of Guam

Ha T. Do, PhD (2015-2016)
Current: Postdoc at Northwestern University

Sanjeev Vernekar, PhD (2011-2017)
Current: Research Scientist at Patheon

Jing Tang, PhD (2008-2018)
Current: Senior Scientist at H. B. Fuller

Jayakanth Kankanala, PhD (2014-2018)
Current: Scientist-Medicinal Chemistry at SPARCBIO  

Visiting Professor

Danae Quirk-Dorr, PhD (05/2013-7/2013)
Professor, Department of Chemistry, Minnesota State University, Mankato, MN 

Phuong-Truc Pham, PhD (07/2013-12/2013)
Associate Professor of Chemistry, Penn State Worthington Scranton