Research Overview
Research Overview
We are a medicinal chemistry group with combined expertise in organic synthesis, molecular modeling, in vitro assay development and compound screening, drug-like property profiling, and chemical probe design and development. Our research focuses primarily on drug discovery against important human viral pathogens, mainly HIV-1, human cytomegalovirus (HCMV), orthopoxvirus (OPXV) and emerging RNA viruses. Our projects typically entail collaborations with virologists and viral structural biologists. We also work closely with our in-house core facilities on biochemistry, computational chemistry, animal PK and toxicology.
Viral Nucleases
We have long been interested in developing novel antivirals targeting metal-dependent viral nucleases which provide key viral functions include genome replication (RNase H of HIV and HBV), cap snatching (endonucleases of influenza virus, bunyavirus, and arenavirus), concatemer resolution (HCMV and OPXV) and proof reading (ExoN). With a signature active site motif of DEDD or PD-E/D-XK, these nucleases share a similar mechanism of catalysis featuring two divalent metal ions, and hence, are susceptible to effective inhibition by metal binding chemotypes, as clinically proven by the FDA-approved flu drug baloxavir.
Orthopoxvirus Drug Discovery
The 2022 global mpox outbreak, primarily driven by clade IIb of mpox virus (MPXV), prompted the WHO to declare it as Public Health Emergency of International Concern twice: in May 2022 and August 2024, as MPXV clade Ib was detected outside Africa, posing a new global health threat. The FDA has approved two drugs for smallpox—tecovirimat and brincidofovir—but against mpox tecovirimat failed to produce clinical efficacy, and efficacy in humans remains unknown for brincidofovir. Toward developing effective MPXV antivirals, particularly novel compounds with unique antiviral mechanisms, we have been using both a phenotypic-based approach with three potent and chemically distinct lead series; and a target-based approach by targeting the viral resolvase required for concatemer resolution.
Targeting HIV-1 Capsid Protein (CA)
HIV capsid protein (CA) CA affects multiple viral replication steps, including uncoating (CA-CA), reverse transcription, nuclear entry (CA-NUP153/CPSF6), integration site selection (CA-CPSF6), and viral assembly (CA-CA). CA is structurally well characterized with with multiple binding sites known. Pharmacologically, the FG-pocket located in CAN is targeted by the best-known CA-binding chemotypes, including the clinically proven lenacapavir. These binders confer extraordinary antiviral potency by competing against host factors NUP153 and CPSF6. However, resistance barrier to LEN can be low. We are exploring novel subtypes for improved resistance profile.
Cancer Therapeutic Sensitization
Tyrosyl DNA phosphodiesterase II (Tdp2) is a DNA repair enzyme implicated in cancer therapeutic resistance and viral genome replication. Protein-DNA adducts featuring a unique 5′ tyrosyl DNA phosphodiester bond are generated transiently during cellular DNA synthesis when topoisomerase 2 (Top2) nicks double strand DNA using its active site tyrosine residue. Clinically important Top2 poisons bind to and stabilize these adducts to induce DNA double-strand breaks (DSBs) and confer anticancer efficacy. Tdp2 repairs these DSBs and causes cellular resistance toward Top2 poisons. Similar tyrosyl-DNA / RNA adducts are formed during the genome replication of certain viruses when the replication is primed by a protein tyrosine. Cleavage of the protein primer off viral DNA / RNA replication intermediates is required for the completion of viral replication cycle and likely carried out by Tdp2. Therefore, chemically inhibiting Tdp2 could provide a viable chemosensitization approach in cancer therapy and contribute critically to understanding the roles of cellular DNA repair pathways in viral genome replication with the potential of new antiviral strategies. Towards validating Tdp2 as a target for cancer therapeutic sensitization and possibly also antiviral drug discovery, we are developing potent Tdp2 active site inhibitors.
Pant, A.; Jagtap, A.; Xie, J.; Belhaouari, D.B.; Xie, W.; Mahoney, J. P.; Wang, Z.Y.; Dsouza, L.; Aboezz, Z. R.; Farkas, T.; Wang, Z.*; Yang, Z.* “Discovery and Characterization of a Hydroxypyridone-3-carboxamide Analog as an Antiviral Lead against Orthopoxviruses” Antimicrob. Agents Chemother. 2026, accepted.
- Kirby, K. A.; McFadden, W. M.; Wang, L.; Du, H.; Zhang, H.; Castaner, A. E.; Lorson, Z. C.; Nafisi, A.; Luchsinger, C.; Hachiya, A.; Cilento, M. E.; Snyder, A. A.; Ravichandran, S. M.; Cai, X.; Tedbury, P. R.; Francis, A. C.; Melikyan, G. B.; Diaz-Griffero, F. R.; Wang, Z.; Sarafianos, S. G.* “Structural, biophysical, and virological mechanistic characterization of HIV-1 capsid-targeting antivirals” bioRxiv 2025.12.30.696960.
- Jamey, N.; Udayanga, D. M. N.; Zhang, H.; Ravichandran, S. M.; Cai, X.; Lorson, Z. C.; McFadden, W. M.; Ryu, W.-H.; Katekar, R.; Xie, J.; Kirby, K. A.; Sarafianos, S. G.*; Wang, Z.*; “Design, synthesis and profiling of highly potent antivirals targeting emerging drug-resistant HIV-1 variants” bioRxiv 2025.12.29. 696941.
- Pant, A.; Jagtap, A.; Xie, J.; Belhaouari, D.B.; Xie, W.; Mahoney, J. P.; Wang, Z.Y.; Dsouza, L.; Aboezz, Z. R.; Farkas, T.; Wang, Z.*; Yang, Z.* “Discovery and Characterization of a Hydroxypyridone-3-carboxamide Analog as an Antiviral Lead against Orthopoxviruses” bioRxiv 2025.12.18.695249.
- Offei, S.; Mahoney, J.; Wang, Z.Y.; Pant, A.; Ryu, W.-H.; Katekar, R.; Xie, J.; Yang, Z.; Wang, Z.* “1-Hydroxy-1,8-napthyridinone (DHN) analogs potently inhibit monkeypox virus resolvase (Mpr)” J. Med. Chem. 2025.
- Pant, A.; Belhaouari, D.B.; Dsouza, L.; Udayanga, D. M. N.; Wang, Z.; Yang, Z. “Ciclopirox suppresses poxvirus replication by targeting iron metabolism” Antiviral Res. 2025, 244, 106290.
- Katekar, R.; Wang, Z.; Xie, J. “Methylation enables sensitive LC-MS/MS quantification of Ciclopirox in mouse pharmacokinetics study” Molecule 2025, 30, 3599.
- Mahoney, J.; Offei, S.; Pant, A.; Wang, Z.; Weiner, B.; Yin, L.; Ryu, W.-H.; Katekar, R.; Williams, J.; Aihara, H.; Yang, Z.; Wang, Z.* “Discovery of small-molecule orthopoxvirus resolvase inhibitors with antiviral activity” J. Med. Chem. 2025.
- Pant, A.; Belhaouari, D.B.; Dsouza, L.; Priyamvada, L.; Wang, Z.; Navarro-Forero, S.; Panayampalli, S. S.; Wang, Z.; Yang, Z. “Suppression of poxvirus replication by SC144” Antiviral Res. 2025, 106204.
- Akther, T.; McFadden, W.M.; Zhang, H.; Kirby, K.A.; Sarafianos, S.G.; Wang, Z.* "Quinazolinone-based Subchemotypes for Targeting HIV-1 Capsid Protein: Design and Synthesis". Med. Chem. Res. 2024.
- Belhadj, Z; Akther, T.; Wang, Z.; Xie, J. “Characterization of a deazaflavin analog as a potent inhibitor of multidrug resistance-associated protein 1” Biomed. Pharmacother. 2024, 178, 117167.
- Akther, T.; McFadden, W.M.; Zhang, H.; Kirby, K.A.; Sarafianos, S.G.; Wang, Z.* "Design and Synthesis of New GS-6207 Subtypes for Targeting HIV-1 Capsid Protein" Int. J. Mol. Sci. 2024, 25, 3734.
- Wang, Z.* “Novel diarylpyrimidine subtypes as HIV-1 nonnucleoside reverse transcriptase inhibitors with improved resistance profile” J Med. Virol. 2024,96:e29553.
- Belhadj, Z; Offei, S.; Jacobson, B. A.; Kratzke, R. A.; Wang, Z.; Xie, J. “Cancer sensitizing effect of deazaflavin analogs is associated with increased intracellular drug accumulation” Eur. J. Pharm. Sci. 2024.106686.
- Jagtap, A; Geraghty, R. J.; Wang, Z.* “Inhibiting HCMV pUL89-C endonuclease with metal-binding compounds” J. Med Chem. 2023, 66, 13874–13887.
- Dsouza, L.; Pant, A.; Offei, S.; Priyamvada, L.; Pope, B.; Satheshkumar, P. S.; Wang, Z.*; Yang, Z.* “Antiviral activities of two nucleos(t)ide analogs against vaccinia and mpox viruses in primary human fibroblasts” Antiviral Res. 2023, 105651.
- Sundararajan, S.; Park, H.; Kawano, S.; Johansson, M.; Lama, B.; Saito-Fujita, T.; Saitoh, N.; Arnaoutov, A.; Dasso, M.; Wang, Z.; Clarke, D. J.; Azuma, Y. “Methylated histones on mitotic chromosomes promote Topoisomerase IIα function for high-fidelity chromosome segregation” iScience 2023.106743.
- Wang, Z.*; Geraghty, R. J. “Viral Nucleases” Viruses 2023, 15, 740.
- He, T.; Edwards, T. C.; Majima, R.; Jung, E.; Kankanala, J.; Xie, J.; Geraghty, R. J.; Wang, Z.* “Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: synthesis and biological characterization” Bioorg. Chem. 2022.106198.
- Jung, E.; Majima, R.; Edwards, T. C.; Soto-Acosta, R.; Geraghty, R. J.; Wang, Z.* “8-Hydroxy-1,6-naphthyridine-7-carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease” ChemMedChem 2022. 202200334.
- 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. 2022.2c00203.
- 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.
- 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. B 2021.
- 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.
- 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.
- 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.
- 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.
- 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 HIV-1 Capsid-Targeting Small Molecules of the PF74 Binding Site” Eur. J. Med. Chem. 2020, 204, 112626.
- 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.
- 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. 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Ajit Jagtap, PhD
Postdoctoral Associate
[email protected]
Nicolas Jamey, PhD
Postdoctoral Associate
[email protected]
Samuel Offei, PhD
Postdoctoral Associate
[email protected]
Syafiq Shahari, PhD
Postdoctoral Associate
[email protected]
- Wang, Z.; Sarafianos, S. G. “Novel antivirals targeting HIV-1 capsid resistant to Lenacapavir”, Provisional Application No.: 63/941,318, filed on 12/15/2025.
- Wang, Z.; Offei, S.; Yang, Z. “Poxvirus antvirals targeting viral resolvases” Provisional Application No.: 63/939,809, filed on 12/12/2025.
- Wang, Z.; Sarafianos, S. G. “Antiviral Compounds”, US 11,850,247B2, issued on 12/26/2023.
- 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).
Active
- 1R01AI183580 NIH/NIAID (Wang / Yang) 06/14/2024-05/30/2029
“Development of novel antivirals against monkeypox virus”
The goal of this grant is to develop three potent and structurally distinct antiviral hits against orthopoxviruses into preclinical drug candidates. - R01AI167356 NIH/NIAID (Sarafianos / Wang) 7/1/2022-6/30/2027
“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. - 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. - R21 AI189247-01 NIH/NIAID (Kirby /co-I Wang) 09/01/2024-08/31/2026
“Novel HIV capsid-targeting antivirals maintain activity against lenacapavir-resistant viruses”.
The goal of this grant is to synthesize and characterize novel compounds that can retain activity against clinically-relevant lenacapavir-resistant mutations toward the goal of improving patient therapies.
Completed
- 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. - 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. - 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. - 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. - 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 - 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.
Postdoctoral Associates
Nirosh Udayanga, PhD (2025)
Thamina Akther, PhD (8/2021-7/2024)
Current: Medtronic
Tianyu He, PhD (04/2019-07/2022)
Current: University of Minnesota, MD Class of 2026
Eunkyung (Kelly) Jung, PhD (01/2019-03/2022)
Current: Scientist II at Abzena
Rajkumar Sahani, PhD (07/2019-08/2021)
Current: Process Chemist at Medicine for all institute, Virginia Commonwealth University
Sameera Senaweera, PhD (10/2018—04/2021)
Current: Senior Scientist (Medicinal Chemistry) at AbbVie
Carlos Ribeiro, PhD (08/2016-07/2019)
Current: Product Developer at Psilo Pharma Inc
Lei Wang, PhD (10/2016—03/2019)
Current: Associate Professor, Department of Pharmaceutical Sciences, Dalian University of Technology, China
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 Professors
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
Student Interns
Haixi Cui (09/2019-05/2020)
Current: PhD student at College of pharmacy
University of Maryland, Baltimore
Raquel Diana Rivero (09/2019-12/2019)
Current: PhD student at Department of Chemistry and Chemical Engineering
UNIVERSIDAD DE LA LAGUNA, Spain
Ruijie Wang (01/2018-05/2018)
Current: Research Assistant at PDX Pharmaceuticals
Yueheng Yuan (01/2018-05/2018)
Current: Graduate student at University of Florida
Kevin Wu (05/2018-08/2018)
Current: PhD student at Chemical Engineering and Material Sciences, UMN
David Zheng (05/2017-08/2017)
Current: PhD student at Chemical Engineering and Material Sciences, UMN
Raymond Niu (05/2016-08/2016)
Current: Student at University of Minnesota
Madelynn Hintsala (05/2015-08/2015)
Current: Pharmacy Intern at Essentia Health Duluth
Phillip Abendroth (01/2015-05/2015)
Current: Associate Quality Scientist at MilliporeSigma
Victor Niu (06/2014-08/2015)
Current: Production Engineer, Facebook
Ryan Baumgartner (09/2010-08/2012)
Current: Senior Chemist at DowDuPont