How targeting a key SARS-CoV-2 enzyme could lead to an antiviral drug

UCSF scientists studying a key enzyme used by the virus that causes COVID-19 have identified chemical building blocks that might eventually be used to make an antiviral drug. The chemical fragments could bind to and disable the enzyme, called the “macro domain,” which is a crucial part of the SARS-CoV-2 virus’s ability to replicate in human cells.

James Fraser, PhD, a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine, led the research effort as part of the UC San Francisco Quantitative Biosciences Institute Coronavirus Research Group (QCRG). QCRG is a project of the UCSF Quantitative Biosciences Institute (QBI), an organized research unit (ORU) that reports through the UCSF School of Pharmacy.

In partnership with the Advanced Light Source at Berkeley Lab and the Stanford Synchrotron Radiation Lightsource at the SLAC National Accelerator Laboratory, the team used X-ray crystallography to map the atomic structure of the macro domain. They then turned to a technique called "fragment soaking" to test hundreds of small chemical fragments for their ability to bind to the macro domain.

Fraser and colleagues are now using a virtual drug discovery platform developed by Brian Shoichet, PhD, a faculty member in the School’s Department of Pharmaceutical Chemistry, to rapidly screen half a billion combinations of these chemical fragments to find drug candidates for COVID-19.

The authors have published their data (Identifying new ligands for the SARS-CoV-2 Macrodomain by Fragment Screening and Multi-temperature Crystallography) to accelerate global efforts to fight the coronavirus pandemic. The open dataset was published in coordination with the Diamond Light Source XChem research group and the lab of Ivan Ahel, PhD, at Oxford University, which simultaneously published a parallel, complementary dataset of macrodomain-bound fragments.

Fraser spoke to the School of Pharmacy’s editorial director, Grant Burningham, about the research and its implications for the fight against COVID-19.

Burningham: How many proteins is the virus making?

Fraser: The virus makes between 20 and 30 proteins. The one we studied is an enzyme that removes a specific modification from human proteins. That modification seems to signal the innate immune system there’s an infection happening. The virus makes this macro domain and eliminates that signal. By inhibiting the macro domain you could counteract the virus, or perhaps reduce the bad effects of the virus and give the body a better chance of fighting it.

Burningham: How did you decide to study this particular enzyme—the macro domain?

Fraser: We are interested in everything the virus does. As part of the QCRG, we literally want to know everything about viral proteins and how they interact with human proteins.

Also, Alan Ashworth [PhD, the president of the UCSF Helen Diller Family Comprehensive Cancer Center] was interested in the function of this protein, which interacts with another group of proteins that Ashworth has studied for years.

The third reason is there are a lot of people studying the spike protein on SARS-CoV-2 and the virus’s protease, and we wanted to go after something that others weren’t looking at. It just so happened that another group in England was doing similar work at the same time.

Burningham: Is there total overlap with their findings or is what they found out more complementary?

Fraser: The work of the two groups is highly complementary. We are both trying to find the starting points for finding inhibitors for this domain. It’s early efforts for both teams. There were some slight differences in the chemical library they used versus the one we used, and there are some technical differences. Their effort actually worked a little better than ours, which we acknowledge and celebrate in our data release post. We ultimately publish together.

But we wanted to share and release the data early. It’s important to set an example of collaboration science in this time of global pandemic.

Burningham: Is using the macro domain something that is novel to coronavirus?

Fraser: No, it is not. Many viruses encode this protein. So it’s possible that an inhibitor could help with other antivirals as well.

Burningham: Are you hopeful about getting a drug that can treat COVID-19 in the near-term?

Fraser: From this effort and for this pandemic, certainly not. The timeline for drug discovery is long, even though we are working at breakneck speed. I hope that other efforts will pan out for this pandemic. We could develop an inhibitor that is useful for the next one; we don’t know how long it will be before another coronavirus hits.

I mentioned how these macro domains are found across many viruses. I grew up in Toronto and a lot of people don’t realize that this is not the first outbreak involving a SARS [severe acute respiratory syndrome] virus, it’s the second. The first hit Toronto in 2003. I don't think this will be the last time that we have a coronavirus problem in the world. The hope would be if we can really push this, by the next pandemic we will have something off-the-shelf that we can use or can be easily modified or put on an accelerated timeline.

Burningham: Any ideas of a timeline for a treatment?

Fraser: We will get better at treating COVID-19, especially late stage treatment, so the mortality will keep falling. But right now, the pandemic is much more a public health problem than a drug development problem.

What motivates me is thinking about the next pandemic. So [that] there is something like what happened with remdesivir, where we can rapidly employ a therapeutic. [Editor’s note: Remdesivir was tried as a treatment for Ebola but is now being used as a treatment for COVID-19.]

Burningham: You’re working at a breakneck speed. Can you really keep working that fast and keep up the enthusiasm?

Fraser: Well, during the shelter in place, only COVID-related research continued on campus. Now that we have opened, people are balancing their old projects and new ones.

The speed may not be quite so breakneck, but the enthusiasm is high because of how important this work is.


Building blocks for COVID-19 antiviral drugs identified in rapid study (UCSF News)

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