Decoding COVID-19: QBI Researchers Pave the Way for New Drug Discoveries to Combat Virus

In the earliest days of the COVID-19 pandemic, as the world scrambled to understand the virus behind a terrifying outbreak that would go on to infect some 100 million Americans and result in over one million deaths, researchers at the UCSF School of Pharmacy’s Quantitative Biosciences Institute (QBI) began rallying scientists from around the world, leading the way toward treatments by reviewing existing drugs and compounds across the medical landscape.

Within weeks of the SARS-CoV-2 genome being sequenced in January 2020, QBI Director Nevan Krogan, PhD, and QBI Chief Operating Officer Jacqueline Fabius formed the QBI Coronavirus Research Group (QCRG), a multidisciplinary coalition that initially involved 42 labs at UCSF and grew to more than 800 scientists from more than 40 institutions across the world.

Members of the QBI Coronavirus Research Group (QCRG) just before a mandatory statewide stay-at-home order was issued on March 19, 2020.

Determined to uncover the virus’s vulnerabilities, the group achieved significant breakthroughs, from being the first to extensively map the host-pathogen protein-protein interaction landscape of SARS-CoV-2 to paving new avenues for developing targeted antivirals.

“We’re setting up infrastructure to tackle this pandemic,” Krogan said in March 2020. “We’re unique in that, here at UCSF, we can do things like this as a group and also pull in talented people from around the world. We’re setting a new paradigm of how science should be done.”

Cracking the viral code

The QCRG was the first to clone all 29 genes of the virus and quickly distributed them to over 400 labs in 40 countries, helping to expedite research on SARS-CoV-2. In late March 2020, the team published a groundbreaking study, authored by 200 collaborating scientists, identifying 332 human proteins that SARS-CoV-2 hijacks to replicate and spread.

This “interactome” map not only revealed how the virus operates but also pointed scientists, including Department of Pharmaceutical Chemistry Professor Brian Shoichet, PhD, and UCSF School of Medicine Professor of Cellular Molecular Pharmacology and Howard Hughes Investigator Kevan Shokat, PhD, toward existing drugs that might disrupt those interactions.

While vaccines ultimately became the world’s best defense against COVID-19, QBI’s work demonstrated the power of host-targeted therapies — drugs that block the body’s interaction with the virus rather than targeting the virus itself. Among the most promising candidates was the anticancer drug plitidepsin, a natural product made by sea squirts, which demonstrated antiviral activity against SARS-CoV-2 by targeting the host protein eEF1A. In a recent collaboration with the Spanish company PharmaMar, plitidepsin was shown to be effective against COVID-19 in a phase III clinical trial.

James Fraser, PhD

In July 2020, a rapid study identified building blocks for COVID-19 antiviral drugs, targeting a part of the virus called the “macrodomain.” QCRG member and Department of Bioengineering and Therapeutic Sciences Chair James Fraser, PhD led the research effort.

“The SARS-CoV-2 macro domain is not as well understood as the virus’s main protease or the spike proteins that other efforts are going after,” Fraser said at the time, leading the research effort as part of the UCSF QCRG Structural Biology Consortium. “We wanted to look where others aren’t looking as heavily and have succeeded in identifying some promising candidates to build drugs that could halt the virus’s ability to replicate and spread in the human body.”

New avenues of drug discovery

Using the latest information about what chemical structures can bind effectively to the macrodomain’s active site, Fraser and colleagues worked with a virtual drug discovery platform developed by Shoichet to rapidly screen half a billion potential drug-like molecules, to find drug candidates that combine several of these potent chemical structures.

Brian Shoichet, PhD

“Fragment-based screening efficiently explores drug chemistry, using building-block ‘fragments’ from which drugs are synthesized,” Shoichet said at the time. “Using advanced x-ray crystallography techniques that the Fraser Lab has pioneered, the studies provide a detailed map of how different drug components should interact with different parts of the viral macrodomain.”

Another milestone came in October 2020, when the QCRG Structural Biology Consortium visualized the SARS-CoV-2 protein Orf9b in atomic detail using cryo-electron microscopy, in an effort led by then QBI Fellow Kliment Verba. “We caught Orf9b in the act of inhibiting a major immune response protein in the cells, Tom70,” said Verba, now an assistant professor of cellular molecular pharmacology in the UCSF School of Medicine. “Our structure is now the basis for a new avenue of drug discovery targeting this interaction.”

A model for future pandemics

When the Biden administration announced $1 billion to support COVID-19 research in March 2021, Krogan — along with QBI Director of Science Portfolio and Strategy Kirsten Obernier, PhD; Bioengineering Assistant Professor Robyn Kaake, PhD; and Senior Scientist Lorena Zuliani Alvarez — spearheaded a proposal that would lead to an initial $67.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), the largest grant in UCSF history.

The grant established QBI as one of nine Antiviral Drug Discovery (AViDD) Centers for Pathogens of Pandemic Concern. With 43 participating labs split evenly between domestic and international and coordinated by the grant’s project manager, Saumya Gopalkrishnan, PhD, QBI’s center stands out as one of the country’s leading programs, generating 56 scientific publications.

Saumya Gopalkrishnan, PhD

“Taking the lessons learned from that effort, we’ve been able to identify liabilities very early on,” said Gopalkrishnan. “And using the testing methods that we have developed, we’re able to make sure that the molecules we synthesize don't have any unwanted side effects, which will create much better therapeutic treatments for vulnerable populations.”

QBI’s collaboration with fellow faculty across the UCSF School of Pharmacy underscored the critical role pharmacy experts play in translating laboratory discoveries into patient-ready treatments.

"It’s important to emphasize how studying one virus can inform others,” said Fabius, who added that QCRG is preparing for future pandemics by expanding its focus to targets against several other viral families.

“A lot of the early work that was done on HIV informed how we approached SARS-CoV-2,” said Krogan. “The more you identify how a virus works using specific tools, technology and methods, the more you can identify how the next one works.”

A disease-agnostic pipeline

Krogan has continued to foster international scientific partnerships. He co-established the Institut Pasteur-UCSF QBI Center of Excellence in Emerging Infectious Diseases. In recognition of his contributions, Krogan was awarded France’s highest honor, the Legion of Honor in 2022 and the Research!America Discovery Innovation Health Prize in 2023. His ongoing work continues to influence the fields of molecular biology and infectious diseases, with a focus on developing comprehensive maps of molecular interactions to inform therapeutic strategies.

“The platform and the international collaborations QBI have established will not only serve as a blueprint to study other viruses but can be applied in a disease-agnostic manner to other diseases as well, such as cancer and neurological disorders, among others,” Obernier said.

More

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• COVID-19 Lessons Learned: ‘Why Aren’t We Working on All Diseases Like This?’

• Spotlight: Nevan Krogan, Breaking Down Silos, The New Era of Science

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

• International Team of Scientists Identifies Common Vulnerabilities Across Coronaviruses