Zhengqiang Wang, Ph.D.

Assistant Professor, Center for Drug Design
Assistant Director, Center for Drug Design

Contact Information

Office: 7-224 Phillips Wangensteen
Phone: 612-626-7025
Fax: 612-625-8154
E-mail: wangx472@umn.edu

Education

B.S., Nankai University, China, 1993
M.S., Peking University, China, 1996
Ph.D., Wayne State University, 2003

Research Summary

Research in my group 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. Currently active projects fall into these areas:

HIV

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 us novel intervention targets; 2) identifying novel chemotypes capable of inhibiting validated therapeutic targets, such as HIV interase (IN) and reverse transcriptase (RT), by combing structure-based design and organic synthesis; and 3) developing novel inhibitors that could accommodate inhibitory activities against two important HIV enzymes, e.g. RT and IN.

HCV

Chronic HCV infection affects an estimated 200 million people globally and causes liver dysfunction and failure. Current standard of care (SOC), the combination of pegylated interferon (peg-INF) and ribavirin (RBV), falls short in achieving SVR in roughly half of treated patients. This low efficacy, along with associated severe adverse effects, has necessitated the development of direct acting agents that are more potent and less toxic than the SOC. Through rational design and in-house compound screening we have identified a number of compounds from a few different molecular scaffolds that are significantly more potent than RBV in HCV replicon assay. Current efforts are on complete SARs of these compounds to identify optimized leads. Further virological and pharmacological characterizations of these leads are being planned to study their mechanism of action (MOA), resistance profiles, antiviral activities, enzyme binding site and pharmacokinetics (PK).

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.

Other Interests

Other than these 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.

Selected Publications

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. and Vince, R. "Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase". J. Med. Chem. 2007, 50, 3416-3419.

Wang Group 2011:

L-R: Ryan Baumgartner, Dr. Zhengqiang Wang, Dr. Jing Tang and Dr. Sanjeev Vernekar