Results from an international collaboration of researchers who announced in March that they had identified 69 drugs that show promise against COVID-19 were published in Nature on April 30th. The now peer-reviewed research gives scientific credence to one of the major efforts aimed at inhibiting the activity of the coronavirus in human cells. The Buck has joined part of the international collaboration and is bringing its expertise in metabolism and aging to the fight against the pandemic.
Nevan Krogan, PhD, the director of the Quantitative Biosciences Institute at the University of California, San Francisco and an adjunct professor at the Buck, led the study. The research was enabled by technology developed in the Krogan lab which maps all the human proteins that viruses use to manipulate our cells. The goal is to understand how each of the promising drugs impacts the biological pathways associated with 332 human proteins now associated with the coronavirus. Some of those pathways are involved in metabolism and aging, and that’s where the Buck comes in.
“When viruses enter our cells, they highjack cellular proteins to replicate,” says Dr. Eric Verdin, President and CEO of the Buck Institute, who is leading of subgroup of researchers looking specifically at the role of metabolic and aging pathways in coronavirus replication. “In the immediate future we hope our efforts will provide clues on which drugs would be most effective against COVID-19. We are also eager to find a beginning explanation of why older adults are more susceptible to complications of the disease.” The drugs identified in the study include both experimental compounds and FDA-approved drugs that are being used to treat unrelated diseases like hypertension, cancer, Parkinson’s disease and schizophrenia.
A number of the promising drugs identified by researchers impact the nutrient-sensing pathway mTORc1 (mammalian Target of Rapamycin) which is implicated in aging and is heavily studied at the Buck. Two of the promising drugs include the diabetes drug metformin and the immune suppressant rapamycin, which extend lifespan and healthspan in animal models of aging. “These are complex drugs. They do involve metabolism but they also have significant side effects on the entire organism,” says Verdin. “That’s why this large collaboration is so important. Scientists are looking at these drugs and pathways from several angles. We need to identify those drugs that shut the virus down, as well as those that boost our natural capacity to fight off viral attacks and develop immunity.”
The research at the Buck also involves a class of proteins called sirtuins, known to regulate many aspects of cellular homeostasis and aging. The Verdin lab has years of experience studying SIRT5 (sirtuin 5) which is believed to play a role in longevity, metabolism, genome stability and diabetes, among others. “Does the virus activate SIRT5 or does it inhibit it, and what is its specific mechanism of action – that’s the information we’re after,” says Verdin. “The drugs identified in the study have the potential to both support COVID-19 infection or block it. Our job is to get to the bottom of what’s going on.”
The Institute is working closely with the Krogan lab and with the lab run by Melanie Ott, MD, PhD, senior investigator at the Gladstone Institute and an adjunct professor at the Buck, to validate initial findings. Marius Walter, a senior postdoc in the Verdin lab, is coordinating the work between the three organizations. The Nature study was co-authored by 125 researchers, an unprecedented collaboration in a field that is known for being competitive. Verdin says each of the co-authors (he is among them) likely has a lab which employs multiple scientists. “I’ve never been involved in something like this. This new way of highly collaborative science is accelerating our work and the discovery process. This is truly exciting, groundbreaking work both in concept and in the approach”