My broad research interests are in the field of signal transduction, protein engineering, chemical biology, and cancer therapeutics. In the past five years, I have been working on development of synthetic biology approaches to manipulate human cell signal transduction cascades to identify new molecular mechanisms and innovative therapeutic strategies. So far, I have published 25 papers in high-profile journals and 3 patents (1 granted, 2 pending). I am also actively engaging in collaborations with researchers from Canada and around the globe in both academic and industrial sectors. I am also appointed in the Canadian Institute for Advanced Research (CIFAR) as an Azrieli Global Scholar in the Molecular Architecture of Life program.
BSc – School of Life Sciences, Beijing Normal University
PhD – Department of Molecular Genetics, University of Toronto
Postdoctoral Fellow - The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto
My research team creates synthetic probes modulating protein-protein interactions to: 1) accelerate understanding of biology, and 2) facilitate development of novel therapeutics. For example, we systematically generated inhibitors and activators for E3 ubiquitin ligases to discover new enzyme catalytic mechanism and new E3 substrates: Zhang et al. Molecular Cell 2016; Gabrielsen et al. Molecular Cell 2017 We also create molecular tools to increase CRISPR-Cas9 genome-editing efficiency: Canny et al. Nature Biotechnology 2018 Finally, we showed that structure-based protein engineering enables development of anti-viral reagents for Middle East respiratory syndrome (MERS) coronavirus: Zhang et al. PLoS Pathogens 2017
Currently, we are interested in the following research projects:
Development of synthetic peptides and proteins to delineate biochemical mechanisms of E3 ubiquitin ligases
Engineering post-translational modifications to probe and rewire DNA damage signaling for cancer therapeutics
Improvement of CRISPR-based gene editing through directed evolution
Veggiani G, Gerpe MCR, Sidhu SS, Zhang W. (2019) Emerging drug development technologies targeting ubiquitination for cancer therapeutics. Pharmacology & Therapeutics 119, 139-154.
Zhang W, Sidhu SS. (2018) Drug development: Allosteric inhibitors hit USP7 hard. Nature Chemical Biology14, 110-111.
Canny MD, Moatti N, Wan LC, Fradet-Turcotte A, Krasner D, Mateos-Gomez P, Zimmermann M, Orthwein A, Juang YC, Zhang W, Noordermeer SM, Seclen E, Wilson MD, Vorobyov A, Munro M, Ernst A, Ng TF, Cho T, Cannon P, Sidhu SS, Sicheri F, Durocher D. (2018) Inhibition of 53BP1 favors homology-dependent DNA repair and increases CRISPR-Cas9 genome-editing efficiency. Nature Biotechnology 36, 95–102.
Gabrielsen M, Buetow L, Nakasone MA, Ahmed SF, Sibbet GJ, Smith BO, Zhang W*, Sidhu SS*, Huang DT*. (2017) A general strategy for discovery of inhibitors and activators of RING and U-box E3 ligases with ubiquitin variants. Molecular Cell 68, 456-470. (*Co-corresponding authors)
Zhang W, Ben-David M, Sidhu SS. (2017) Engineering cell signaling modulators from native protein-protein interactions. Current Opinion in Structural Biology 45, 25-35.
Zhang W, Bailey-Elkin BA, Knaap RCM, Khare B, Dalebout TJ, Johnson G, van Kasteren PB, McLeish N, Gu J, He W, Kikkert M, Mark BL, Sidhu SS. (2017) Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants. PLoS Pathogens 13(5): e1006372. https://doi.org/10.1371/journal.ppat.1006372
Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS. (2016) System-wide modulation of HECT E3 ligases with selective ubiquitin variant probes. Molecular Cell 62, 121-36. ⌘ Highlighted in the issue with accompanied preview: Canadeo LA, Huibregtse JM. (2016) A billion ubiquitin variants to probe and modulate the UPS. Molecular Cell 62, 2-4.
Zhang W, Durocher D. (2010) De novo telomere formation is suppressed by the Mec1-dependent inhibition of Cdc13 accumulation at DNA breaks. Genes & Development 24, 502-15. ⌘ Highly recommended by Drs. Virginia Zakian (Princeton), David Shore (Geneva), and Katherine Friedman (Vanderbilt) on Faculty of 1000. ⌘ Featured as “Top 7 in Cancer Biology” in March 2011 by The Scientist magazine®