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Interview with Dr. Wei Zhang

📷 SynBio Canada

Journalist: Rajpreet Chakkal

Raj: Welcome to SciSection, my name is Raj, I'm a journalist for the SciSection radio show broadcasted on CFMU 93.3 FM. We are here today with Doctor Wei Zhang, thank you for taking the time to meet with us and we welcome you onto our show!

Dr. Zhang: Thank you for having me here.

Raj: Can you tell our listeners a bit about your field of research and what exactly is it that you do?

Dr. Zhang: Sure, my field of research is protein engineering and the goal of my lab is to develop probes. So, probes are synthetic molecules and by synthetic, I mean that they are not appearing anywhere in nature. So, we're creating new molecules to manipulate human cell signal transduction and the goal is to identify novel biology and in the meantime create novel therapeutic strategies targeting cancer and infectious diseases. My lab currently has three active research projects the first one being engineering protein-protein interactions in DNA repair and the second is the development of inhibitors or disease-related enzymes with a particular focus on protein ubiquitination and the third, and the most we think that has a high-risk high reward project is induced proximity for targeted protein degradation and if that is successful we should be able to target in any undruggable target in human cells, thank you.

Raj: That's great and yeah so after looking into it, you guys have had lots of success at the Zhang Lab and so one major gene-editing tool is CRISPR CAS9 and your team has created a tool to increase its efficiency. Can you explain a bit about the modifications you made and how they increase the function of efficiency?

Dr. Zhang: That's right, so that project is actually a collaboration project with my former PhD mentor Doctor Dan Desrochers in the University Toronto and also that was the work I did during my postdoc in Dave Sidhu’s lab in Toronto. It's actually one of my first endeavors in engineering protein-protein corrections in DNA repair because for CRISPR, CRISPR is related to DNA repair in many ways as you know at least most of the CRISPR gene editing applications are based on creating a break in the genome and then and then repair it using the template that researchers provided to them. So we know that 53BP1 the protein of interest is a regulator for them, what it means is that 53BP1 controls which DNA repair pathway that's a DNA damage is prepared by the cells so we want that to go through the homologous recombination role because that way it can be precisely repaired using the template but the cells, especially human cells, can repair it using another repair pathway called nonhomologous end joining. So, 53BP1 if it inhibits it will lead to precision repair and that is important for the gene-editing 'cause we want the gene editing to be very accurate and we don't want any mutation involved in that process. So what I did is I generated inhibitor for 53BP1 and we called it I53 and that inhibitor can block accumulation of 53BP1 at sites of DNA damage and then the effect afterwards is to improve the CRISPR CAS9 mediated gene targeting an gene conversion and the fold of improvement is about 6 fold. That may sound not like a big deal but in certain gene-editing applications for example in animals, that can lead to a dramatic game-changer for precision gene editing. So, I think this would really highlight the robustness of our protein design engineering platform and that's why in my own lab I've now employed this potential targeting DNA damage to different applications including further improving CRISPR CAS9 based gene editing.

Raj: For sure that's great, and so you're also now a part of a team that's dealing with COVID-19 and so how far have you come into the research of COVID-19, and how long is there like a journey ahead?

Dr. Zhang: Yeah, you know the whole word is backed by COVID and we as researchers we have you know, we feel the need of doing something for the COVID research. I know that you know at McMaster you guys are doing a lot of work there and for me personally I'm involved in two different teams actually. One is led by Dr. Dave Sidhu, my former postdoc mandatory in Toronto, and what we are doing there is to create protein-based inhibitors for the SARS COV 2 protease. The SARS COV 2 protease is important for trimming the viral party proteins and that is essential for the viral replication itself. It has another function; the protease has another roll of hijacking the human immune response and so the inhibitors are supposed to hit two birds with one stone by targeting different functions of these proteins in order to stop the viral replication. So far we have already identified potent and specific inhibitors but that is protein-based and so we are in the process of confirming its cellular activity and the next step is to use small molecule displacement screens to identify chemical compounds that can be moved to therapeutics much quicker than protein-based biologics because that will have issues with delivery and other things that are the project essentially in led by Dr. Dave Sidhu. For me, I mainly provide consulting because that is based on my postdoc work. Another smaller project that’s led by me and with collaboration with faculty a member named Dr. Yi Sheng at York University. What we're doing is we want to directly screen for a natural compound and FDA-approved drugs to inhibit this same protease and it's actually supported by my University of Guelph and with a special donation from UofG alumni. So, what we're doing for this project is to use in silico screening methods which are structure-based and to identify putative inhibitors first and then followed by the verification of their activity in the invasion itself. So far, we have identified one type of natural compounds that are really effectively inhibiting that protease and we're in the process of confirming that by structural biology and also cell biology. Although we have made some progress currently, but it's still far away from therapeutics and I know you probably heard of and in the audience probably know that there is a lot of research done on vaccine an antibody site and in terms of the small molecule therapeutics and protein-based therapeutics which we are working on if any compound is confirmed is still half a year away from medicinal chemistry work and probably one year for animal work before talking about clean controls. That can take much longer so we're still far away from the therapeutics, but we are trying our best.

Raj: You trying to create something that would inhibit this protease right and so would that ultimately be the step forward into going towards vaccination as you just trying to inhibit something?

Dr. Zhang: Yes we're trying to inhibit the protease so in general, we have two ways of battling this virus. One is a vaccine and the other is therapeutics, so what we are doing is in the therapeutics. What we're doing has nothing to do with vaccine 'cause vaccine is 2 using different methods to have a non-infective virus that can stimulate human cells to have the antibodies that are able to battle in the real virus once they’re affected. Therapeutics is more for the patient who is already infected with a virus because we want to cure them, we want to make them better. We want to reduce mortality, so what we're doing will ultimately contribute to the therapeutics and to the clinics that are future drugs that will be used in the hospital to treat the patients.

Raj: Okay and so now being part of a team that's trying to understand and diagnose COVID-19 how does this research differ from your past experiences with viruses such as like MERS?

Dr. Zhang: Right, so the first project I mentioned at the UofT, that project is essentially entirely based on my postdoc that targets MERS, I mean M-E-R-S COV, when MERS came out it was called Middle East Respiratory Syndrome Corona Virus and emerged after SARS which you know we saw the outbreak in 2002-2003. Around 2008-2010 we saw the limited outbreak of MERS which has much higher mortality but has lower spreads compared to for example SARS COV 2 and what we're doing there is the same strategy we are using to target SARS COV 2. MERS is to develop protein-based inhibitors that are hijacking a particular protein-protein correction of that protease with ubiquitin which is a cellular protein. What we are doing is to mimic that interaction and create new molecules based on the ubiquitin scuffle and creating these synthetic ubiquitin variants which we can run. The characteristic of that synthetic molecule is that it binds much better than wildtype proteins so when we express that in the south it can disable this protease for its de-ubiquitin activity and the de-isolation activity which are two activities that are used to hijack the human immune response. Most importantly, it can disable its activity to cleave viral polyproteins because MERS-COV, SARS-COV, and SARS-COV 2 they’re all RNA viruses. That means is that their RNA is translated into a long protein and they need the protease to cut it into functional units because without protease the virus cannot replicate in human cells. Other inhibitors precisely inhibit that function and we have passed the effect of these inhibitors in the suppression of the replication of live MERS virus so we collaborated this with a level 4 facility in the Netherlands and remarkably in 48 hours these inhibitors shut down the viral replication and no viral titers could be detected in cells. So, this work was done in 2017, we targeted immerse another virus called Crimean-Congo Hemorrhagic Fever (CCHF) virus. CCHF has a much higher mortality rate so we target two different viruses using this same concept and so we think we established a platform that can produce antiviral agents that can be used for plants, animals, and humans to target in all types of host-pathogen interactions. So, the work I mentioned that led by Dr. Sidhu at the University of Toronto is basically based on this work and we have already made good progress.

Raj: That’s great, so COVID has affected many other industries, and is there any significant impact that it’s made on the research industry in terms of supplies or maybe putting other researches that you have going on, on hold to prioritize this?

Dr. Zhang: First, back in March and April definitely yes, and we can see a shortage of gloves and tips and all the reagents that can potentially be used for diagnostics for testing. We as a research lab actually are involved in donating some of the lab materials including the shields, gloves, all types of things like even PCR machines I know that some labs did donate to local hospitals and test centers but since you know our lab got shut down for about four months and since then we have started to see the supplies are stable.

Raj: That's great! That's the end and it was a pleasure to have you on the show, Dr. Zhang, thank you for joining us today!

Dr. Zhang: Thank you.

Raj: Alright guys that's it for this week of SciSection make sure to check out our podcast available on global platforms for our latest interviews.


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