Jun Wang, PhD
The Wang laboratory is interested in developing novel chemical tools, including small molecules and miniproteins, to help better us understand biology, and in turn use that knowledge to design better drugs to fulfill unmet medical needs.
The Wang laboratory consolidates expertise ranging from organic synthesis, peptide chemistry, rational drug design, molecular biology, electrophysiology, virology, to cell imaging, all in the same laboratory. This multi-disciplinary environment enables researchers in the Wang laboratory to explore various aspects of lead discovery. We are engaged in both rational drug design and high-throughput screening to discover the first-in-class chemical probes/drug candidates.
As a practical application, we are interested in designing broad-spectrum antivirals targeting influenza viruses, especially multi-drug-resistant influenza viruses. Currently, we are exploring both viral proteins and host factors as antiviral drug targets. As an example, we have designed the first-in-class M2-S31N inhibitors, and these compounds have shown potent antiviral activity against multiple human influenza A strains, including the ones that are resistant to oseltamivir. In another example, we have identified several hits from a high-throughput screening campaign, and they have shown broad-spectrum antiviral activity against both influenza A and B strains with mechanisms distinct from that of known antiviral drugs. We believe that these novel hits will not only lead us to discover novel viral replication signaling pathways and open new opportunities for antiviral drug design, but also help us better understand the mechanism of drug resistance. In terms of combating antiviral drug resistance, we have no bias towards direct-acting antivirals versus host-targeting antivirals. We believe each class of antivirals has certain advantages and the ultimate solution to drug resistance might be combination therapy.
We are also interested in designing inhibitors targeting ion channels and use them as tools to understand their structures, functions, and dynamics. Towards this goal, we are developing novel functional assays suitable for high-throughput screening of ion channel blockers. As an example, we have developed the yeast-growth restoration assay and have identified several novel chemotypes for the M2 proton channel from a high-throughput screening. We are now adapting this assay for the BM2 proton channel. In parallel, we are also designing channel blockers using computational methods, such as molecular dynamics simulation and molecular docking. Other targets of interest include voltage-gated proton channel, acid-sensing ion channel, and chloride ion channel.
The Wang laboratory always welcomes enthusiastic persons to join our team. Please email Dr. Wang at firstname.lastname@example.org for job opportunities. Undergraduate students are particularly encouraged to apply.
Visit the lab website.
BS Chemistry, Wuhan University, China, 2003
MS Chemistry, National University of Singapore, Singapore, 2006
PhD Chemistry, University of Pennsylvania, 2010
1. Balgi, A. D.; Wang, J.; Cheng, D. Y.; Ma, C.; Pfeifer, T. A.; Shimizu, Y.; Anderson, H. J.; Pinto, L. H.; Lamb, R. A.; DeGrado, W. F.; Roberge, M., Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay. PLoS One 2013, 8 (2), e55271.
2. Mao, L.; Wang, J.; DeGrado, W. F.; Inouye, M., An assay suitable for high throughput screening of anti-influenza drugs. PLoS One 2013, 8 (1), e54070.
3. Wang, J.; Ma, C.; Wang, J.; Jo, H.; Canturk, B.; Fiorin, G.; Pinto, L. H.; Lamb, R. A.; Klein, M. L.; DeGrado, W. F., Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus. J. Med. Chem. 2013, 56 (7), 2804–2812.
4. Wang, J.; Wu, Y.; Ma, C.; Fiorin, G.; Wang, J.; Pinto, L. H.; Lamb, R. A.; Klein, M. L.; Degrado, W. F., Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus. Proc. Natl. Acad. Sci. USA 2013, 110 (4), 1315–1320.
5. Williams, J. K.; Tietze, D.; Wang, J.; Wu, Y.; DeGrado, W. F.; Hong, M., Drug-induced conformational and dynamical changes of the S31N mutant of the influenza M2 proton channel investigated by solid-state NMR. J. Am. Chem. Soc. 2013, 135 (26), 9885–9897.
6. Cady, S. D.; Wang, J.; Wu, Y.; DeGrado, W. F.; Hong, M., Specific binding of adamantane drugs and direction of their polar amines in the pore of the influenza M2 transmembrane domain in lipid bilayers and dodecylphosphocholine micelles determined by NMR spectroscopy. J. Am. Chem. Soc. 2011, 133 (12), 4274–4284.
7. Wang, J.; Ma, C.; Balannik, V.; Pinto, L. H.; Lamb, R. A.; Degrado, W. F., Exploring the requirements for the hydrophobic scaffold and polar amine in inhibitors of M2 from influenza A virus. ACS Med. Chem. Lett. 2011, 2 (4), 307–312.
8. Wang, J.; Ma, C.; Fiorin, G.; Carnevale, V.; Wang, T.; Hu, F.; Lamb, R. A.; Pinto, L. H.; Hong, M.; Klein, M. L.; DeGrado, W. F., Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2. J. Am. Chem. Soc. 2011, 133 (32), 12834–12841.
9. Wang, J.; Ma, C.; Wu, Y.; Lamb, R. A.; Pinto, L. H.; DeGrado, W. F., Exploring organosilane amines as potent inhibitors and structural probes of influenza A virus M2 proton channel. J. Am. Chem. Soc. 2011, 133 (35), 13844–13847.
10. Wang, J.; Qiu, J. X.; Soto, C.; DeGrado, W. F., Structural and dynamic mechanisms for the function and inhibition of the M2 proton channel from influenza A virus. Curr. Opin. Struct. Biol. 2011, 21 (1), 68–80.
11. Cady, S. D.; Schmidt-Rohr, K.; Wang, J.; Soto, C. S.; Degrado, W. F.; Hong, M., Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. Nature 2010, 463 (7281), 689–692.
12. Leiding, T.; Wang, J.; Martinsson, J.; DeGrado, W. F.; Arskold, S. P., Proton and cation transport activity of the M2 proton channel from influenza A virus. Proc. Natl. Acad. Sci. USA 2010, 107 (35), 15409–15414.
13. Balannik, V.; Wang, J.; Ohigashi, Y.; Jing, X.; Magavern, E.; Lamb, R. A.; Degrado, W. F.; Pinto, L. H., Design and pharmacological characterization of inhibitors of amantadine-resistant mutants of the M2 ion channel of influenza A virus. Biochemistry 2009, 48 (50), 11872–11882.
14. Wang, J.; Cady, S. D.; Balannik, V.; Pinto, L. H.; DeGrado, W. F.; Hong, M., Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. J. Am. Chem. Soc. 2009, 131 (23), 8066–8076.