Zhengqiang Wang, PhD

Expertise

Organic synthesis, computer-aided inhibitor design, assay development and compound screening, chemical probes design and synthesis, in vitro ADME and animal PK.

Research Summary

Research in my group concerns primarily the design and synthesis of small organic molecules to probe / inhibit protein functions. We are particularly interested in protein targets implicated in the replication of various viruses as well as cellular DNA repair pathways. Our efforts are typically aligned with early drug discovery events, including target validation, lead generation, optimization and characterization, and pharmacokinetics (PK). Currently projects fall into these areas:

Human Immunodeficiency Virus (HIV)
Clinical management of HIV / AIDS relies solely on successful Highly Active Anti-Retroviral Therapy (HAART). Antivirals with novel mechanism of action and / or novel resistance profile are key to sustainable HAART. Toward these ends, we are currently exploring two distinct approaches:

1. Targeting HIV reverse transcriptase associated RNase H (grant support: NIAID R01AI100890). As a sub-domain of reverse transcriptase (RT), RNase H remains the only HIV encoded enzymatic function yet to be targeted by any known antiviral drugs (Figure 1). While many compounds have been reported to inhibit HIV RNase H biochemically, few were found to inhibit HIV in cell culture and none is known to confer antiviral phenotype via RNase H inhibition. We are conducting major medicinal chemistry efforts aligned toward validating RNase H as an antiviral target against HIV. 
2. Designing capsid-targeting antivirals (grant support: NIAID R01AI120860). The HIV-1 capsid protein (CA) plays critical roles in multiple steps of the viral replication cycle, including uncoating, reverse transcription, nuclear entry, sites of integration, and assembly. These critical functions are regulated through CA interactions and core stability. Small molecules can increase or decrease the core stability by disrupting CA interactions, and hence confer antiviral phenotypes in a unique way. Our current medicinal chemistry focuses on the design and synthesis of peptidomimetics for probing the structure and functions of HIV CA. 

Hepatitis B Virus (HBV) (grant support: NIAID R01AI121315)
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). 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).  

Human Cytomegalovirus (HCMV) UL89 (Grant support: UMN CDD Seed and Research Development Grant)

HCMV infection poses a major health threat to immunocompromised individuals such as newborns, HIV and transplant patients. Current drugs all target viral polymerase and suffer from poor efficacy, toxicity and resistance. Hence, there is a pressing need for antivirals with a novel mechanism of action. We are currently targeting the C-terminal endonuclease function of the viral protein UL89 which is important for proper genomic DNA packaging and virus assembly. 

Tyrosyl DNA phosphodiesterase II (TDP2) (grant support: AHC AFRD) TDP2 is a newly discovered DNA repair enzyme and the only known human enzyme capable of cleaving 5’-tyrosyl DNA adducts. It is implicated in the chemotherapeutic resistance of topoisomerase 2 (Top2) poisons, as well as the genome replication of hepadnaviruses (e.g. HBV) and picornaviruses. Inhibiting TDP2 provides pathways toward Top2 poison sensitization in cancer therapy and host-targeting antivirals. We are currently pursuing medicinal chemistry for potent and selective TDP2 inhibitors targeting its active site. 

• He, T.; Edwards, T. C.; Xie, J.; Aihara, H.; Geraghty, R. J.; Wang, Z.* "4,5-Dihydroxypyrimidine methyl carboxylates, carboxylic acids, and carboxamides as inhibitors of human cytomegalovirus pUL89 endonuclease" J. Med. Chem. 2022, Accepted.
• Sahani, R. L.; Akther, T.; Cilento, M. E.; Castaner, A. E.; Zhang, H.; Kirby, K. A.; Xie, J.; Sarafianos, S. G.; Wang, Z.* "Potency and metabolic stability: a molecular hybrid case in the design of novel PF74-like small molecules targeting HIV-1 capsid protein” RSC Med. Chem. 2021, DOI: https://doi.org/10.1039/D1MD00292A.
• Senaweera, S.; Edwards, T. C.; Kankanala, J.; Wang, Y.; Sahani, R. L.; Xie, J.; Geraghty, R. J.; Wang, Z.* "Discovery of N-Benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV)” Acta Pharm. Sin. B2021,DOI: https://doi.org/10.1016/j.apsb.2021.08.019
• Wang, L.; Edwards, T. C.; Sahani, R. L.; Xie, J.; Aihara, H.; Geraghty, R. J.; Wang, Z.* "Metal binding 6-arylthio-3-hydroxypyrimidine-2,4-diones inhibited human cytomegalovirus by targeting the pUL89 endonuclease of the terminase complex” Eur. J. Med. Chem. 2021, (Abstract).
• Sun, Q.; Levy, R.; Kirby, K. A.; Wang, Z.; Sarafianos, S. G.; Deng, N. "Molecular Dynamics Free Energy Simulations Reveal the Molecular Basis of Antiviral Resistance through the M66I HIV-1 Capsid Mutation” Viruses 2021, 13, 920.
• Senaweera, S.; Du, H.; Zhang, H.; Kirby, K. A.; Tedbury, P. R.; Xie, J.; Sarafianos, S. G.; Wang, Z.* "Discovery of new small molecule hits as hepatitis B virus capsid assembly modulators: structure and pharmacophore-based approaches” Viruses 2021, 13, 770.
• Xie, J.*; Wang, Z.* “Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment” Acta Pharm. Sin. B 2021, (Abstract).
• Sahani, R. L.; Diana-Rivero, R.; Vernekar, S. K. V.; Wang, L.; Du, H.; Zhang, H.; Castaner, A. E.; Casey, M. C.; Kirby, K. A.; Tedbury, P. R.; Xie, J.; Sarafianos, S. G.; Wang, Z.* "Design, synthesis and characterization of HIV-1 CA-targeting small molecules: conformational constraint of PF74” Viruses 2021, 13, 479.

• Senaweera, S.; He, T.; Cui, H.; Aihara, H.; Wang, Z.* “4-Benzylideneisoquinoline-1,3(2H,4H)-diones as tyrosyl DNA phosphodiesterase 2 (TDP2) inhibitors” Med. Chem. Res. 2020. 30, 371-386. (Abstract)
• Oshima, K.; Zhao, J; Perez-Duran, P.; Brown, J. A.; Patino-Galindo, J. A.; Chu, T.; Quinn, A.; Gunning, T.; Belver, L.; Ambesi-Impiombato, A.; Tosello, V.; Wang, Z.; Rabadan, R.; Ferrando, A. “Mutational and functional genetics mapping of chemotherapy resistance mechanisms in relapsed acute lymphoblastic leukemia” Nat. Cancer. 2020, 1, 1113-1127.
• Wang, L.; Casey, M.; Vernekar, S. K. V.; Sahani, R. L.; Kirby, K. A.; Du, H.; Zhang, H.; Tedbury, P. R.; Xie, J.; Sarafianos, S. G.; Wang, Z.* " Novel Small Molecules Targeting the PF74 Binding Site: Balance of Potency and Metabolic Stability” Acta Pharmaceutica Sinica B 2021, 11, 810-822. (Abstract)
• Wang, L.; Casey, M.; Vernekar, S. K. V.; Sahani, R. L.; Kirby, K. A.; Du, H.; Zhang, H.; Tedbury, P. R.; Xie, J.; Sarafianos, S. G.; Wang, Z.* " Novel HIV-1 Capsid-Targeting Small Molecules of the PF74 Binding Site” Eur. J. Med. Chem. 2020, 204, 112626. (Abstract)
• Vernekar, S. K. V.; Sahani, R. L.; Casey, M.; Kankanala, J.; Wang, L.; Kirby, K. A.; Du, H.; Zhang, H.; Tedbury, P. R.; Xie, J.; Sarafianos, S. G.; Wang, Z.* "Toward Structurally Novel and Metabolically Stable HIV-1 Capsid-Targeting Small Molecules” Viruses 2020, 12, 452; doi:10.3390/v12040452 
• Wang, L.; Casey, M.; Vernekar, S. K. V.; Do, H. T.; Sahani, R. L.; Kirby, K. A.; Du, H.; Hachiya, A.; Zhang, H.; Tedbury, P. R.; Xie, J.; Sarafianos, S. G.; Wang, Z.* " Chemical Profiling of HIV-1 Capsid-Targeting Antiviral PF74” Eur. J. Med. Chem. 2020. DOI: 10.1016/j.ejmech.2020.112427
• Dang, X.; Ogbu, S. C.; Zhao, J.; Nguyen, L. N. T.; Cao, D.; Nguyen, L. N.; Khanal, S.; Schank, M.; Thakuri, B. K. C.; Wu, X. Y.; Morrison, Z. D.; Zhang, J.; Li, Z.; Gazzar, M. E.; Ning, S.; Wang, L.; Wang, Z.; Moorman, J. P.; and Yao, Z. Q “Inhibition of topoisomerase IIa induces telomeric DNA damage and T cell dysfunction in chronic viral infections” Cell Death Dis. 2020, 11, 196.
• Wang, L.; Sarafianos, S. G. and Wang, Z.* “Cutting into the Substrate Dominance: Pharmacophore and Structure-Based Approaches toward Inhibiting HIV Reverse Transcriptase-Associated Ribonuclease H” Acc. Chem. Res. 2020, 53, 218-230.
• Kiselev, E.; Ravji, A.; Kankanala, J.; Xie, J.; Wang, Z. and Pommier, Y. “Novel deazaflavin tyrosyl DNA phosphodiesterase 2 (TDP2) inhibitors” DNA Repair 2019, 85, 102747.
• Xi, Z.; Wang, Z.; Sarafianos, S. G.; Myshakina, N. S.; Ishima, R. “Determinants of Active-Site Inhibitor Interaction with HIV-1 RNase H” ACS Infect. Dis. 2019, 5, 1963-1974.
• Wang, Z.* “Challenges and opportunities in hepatitis B research” ACS Infect. Dis., 2019, 5, 652-654.
• Kankanala, J.; Ribeiro, C.; Shi, K.; Kurahashi, K.; Kiselev, E.; Ravji, A.; Pommier, Y.; Aihara, H.; Wang, Z.* "Novel deazaflavin analogues potently inhibited tyrosyl DNA phosphodiesterase 2 (TDP2) and strongly sensitized cancer cells toward treatment with topoisomerase II (TOP2) poison etoposide " J. Med. Chem., 2019, 62, 4669-4682. Abstract.
• 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, 390-399.
• 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., 2019, 29, 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., 2019, 5, 750-758. Abstract
• 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., 2018, 164, 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, 1658-1633.
• 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 2018, 3, 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. 2018, 152, 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

ACTIVE

1) R01 AI120860 NIH/NIAID (Sarafianos / Wang) 07/01/2021-06/30/2026
“Development of HIV capsid-targeting antivirals that affect immune response by modulating capsid stability and have improved resistance profiles”.
The goal of this grant is to advance the understanding of the structural basis of HIV capsid (CA) core stability and to discover CA-targeting antivirals with improved pharmacological properties, high potency, and improved resistance profiles.

2) R01AI136982 NIH/NIAID (Geraghty / Wang) 01/25/2019-01/24/2024
“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.

3) R01AI121315 NIH/NIAID (Sarafianos / Wang) 06/14/2016-06/13/2022
“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.

PENDING (Scored within payline)

1) R01AI167356 NIH/NIAID (Sarafianos / Wang) 9/1/2021-08/31/2026
“Discovery of SARS-CoV-2 antivirals using a replicon assay”
The goals of this grant are to identify SARS-CoV-2 antiviral hits via screening chemical libraries using replicon plasmid systems and SARS-CoV-2 replicon-expressing cell lines, and to optimize these hits via iterative SAR and ADME property profiling.

COMPLETED

1) R01AI120860 NIH/NIAID (Sarafianos / Wang) 06/15/2015-06/14/2021
“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.

2) R01AI100890 NIH/NIAID (Sarafianos / Wang) 07/01/2012-06/30/2018
“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. Currently on no cost extension.

3) Research Development and Seed Grant (Wang) 07/01/2012-06/30/2014
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

4) FRD#23. Faculty Research Development Grant (Aihara / Wang) 07/01/2014-06/30/2016
Academic Health Center, University of Minnesota
“Structure-Based Discovery of Tyrosyl DNA Phosphodiesterase 2 (TDP2) Inhibitors”
The goal of this grant is to discover novel hTdp2 inhibitors and obtain their co-crystal structures with hTDP2 to allow understanding on inhibitory mechanism and provide a platform for TDP2 drug discovery efforts.

• Wang, Z.; Sarafianos, S. G. “Antiviral Compounds”, provisional # 63008320, filed on 04/09/2020
• Wang, Z.; Kankanala, J.; Pommier, Y. “Compounds for Cancer Chemotherapeutic Sensitization” U. S. Patent No. 10617706, issued 04/124/2020
• Sarafianos, S. G.; Huber, A. D.; Wang, Z.; Tang, J. “Inhibitors of Hepatitis B Virus Targeting Capsid Assembly” US 62/564,865, 09/27/2017
• Wang, Z. “3-Hydroxypyridine-2,4-dione-5-carboxamides as potent inhibitors of HIV” US 10,117,871 B2, issued on 11/06/2018
• Marchand, C.; Pommier, Y.; Wang, Z.; Sirivolu, V. R. “Thioxothiazolidinone Derivatives Useful as Inhibitors of Tdp1”, WO/2013/055771 (Oct. 10, 2012).
• Wang, Z.; Geraghty, R. J.; Vince, R.; Tang, J. “N-Hydroxypyrimidine-2,4-diones as Inhibitors of HIV and HCV”, WO2012047993 A2 (Oct. 5, 2010).