Value Of Drug Repurposing May Lie In Host-Directed Therapies

By Deborah Borfitz 

May 10, 2021 | The pandemic has showcased the best and the worst of the scientific enterprise, including the silos that exist between disciplines as well as the extraordinary speed of discovery when the barriers come down. Exhibit A comes from the University of California, San Francisco (UCSF), whose Quantitative Biosciences Institute (QBI) spearheaded a six-nation collaborative around COVID-19 that now has 26 potential treatments in clinical trials. 

The unprecedented level of cross-disciplinary teamwork, inclusive of 25 institutions and 10 industry partners, effectively unblinded researchers to commonalities across genes and disease areas, according to QBI Director Nevan Krogan, Ph.D., who is also a professor in the department of cellular and molecular pharmacology. It will take concerted effort to maintain that “infrastructure and spirit” to better prepare for the next pandemic—or to find cures for perennial problems such as breast cancer and Alzheimer’s disease.   

Drug repurposing has been one of the focal points of the QBI Coronavirus Research Group (QCRG), both because time was of the essence and many anti-cancer drugs on the market proved effective against COVID-19, Krogan says. The same genes being mutated in cancer are being hijacked by SARS-CoV-2, just as Alzheimer’s disease and the Zika virus share the same Achille’s heel. 

This is not terribly surprising, he adds, since viruses are “very smart and evolved to attack cells.” But scientists are going to miss the signs if they are not comparing notes. 

Without coordination, both time and funding may be wasted, says Krogan. Hundreds of repurposed drugs are now in clinical trials for COVID-19, but many of them work through a process called phospholipidosis (a discovery made by fellow QCRG scientist Brian Shoichet, DOI: 10.1101/2021.03.23.436648) that likely has no value in combatting the virus, he adds. “Hydroxychloroquine falls in that category. Do we really need 450 clinical trials on hydroxychloroquine or just one?” 

Through the pandemic-inspired Accelerating COVID‑19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership, the National Institutes of Health has been funding studies of repurposed drugs under a master protocol. Krogan says he applauds efforts like this by prioritizing the drugs that get into clinical trials. “We just need to see more of that.”  

Other recently reported collaborative efforts include a large-scale human genetics study conducted by researchers from VA Boston Healthcare System, the University of Cambridge, EMBL’s European Bioinformatics Institute, and Istituto Italiano di Tecnologia to identify drugs targeting IFNAR2 and ACE2 proteins that could be repurposed for early management of COVID-19 to prevent disease progression.  

The artificial intelligence platform of Cyclica was also deployed to discover another potential COVID-19 drug from repurposing—in this case capmatinib (Tabrecta), Novartis MET inhibitor used to treat patients with non-small cell lung cancer—in a partnership involving Ryerson University and the University of Toronto’s Vector Institute. 

The real value in drug repurposing comes from targeting human proteins with host-directed therapies, Krogan says. “Viruses mutate very quickly, but people don’t.” A virus is never going to mutate enough to overcome its reliance on human proteins to infect cells, reducing concerns about resistance. 

So, while many pharmaceutical companies may opt to conduct largescale drug screens to identify repurposing candidates, QBI is sticking to its data-driven approach to drug discovery that starts with unraveling the underlying biology by documenting how the proteins of a virus interact with proteins in the cells of its target human host. 

The approach “takes a little longer initially, but the long-term consequences are much more profound,” says Krogan. “Our hit rate is much higher in terms of what is of value and we… are so much further ahead in terms of tweaking the compound [for improved potency].” 

Protein Interaction Map  

QBI created a Host-Pathogen Map Initiative jointly with the Center for Emerging and Neglected Disease at UC-Berkeley several years ago to create maps of the contact points between viral and human proteins to understand how problem viruses like Ebola and Zika “hijack, rewire, and infect human cells,” Krogan says. But the pandemic enlarged the effort to more than 200 researchers worldwide singularly focused on finding drug candidates to wipe out infection by SARS-CoV-2. 

The launch of QCRG began internally by establishing a “web of interactions” among over 40 uniquely skilled groups of scientists, which were broken into 12 subgroups specific to different biological processes and technologies, he says. Proteomics, cell biology, genetics, virology, structural biology, molecular biology, biochemistry, microscopy, bioinformatics, and clinical specialists all quickly came together—“partially out of fear”—only to learn how connected they really were.  

As a first step, the QCRG constructed a SARS-CoV-2 protein interaction map revealing 66 druggable human proteins or host factors targeted by 69 compounds—including 29 already approved by the Food and Drug Administration and another 12 in clinical trials. The group is particularly excited about the potential of two translational inhibitors that were subsequently shown to be highly effective against SARS-CoV-2 in clinical trials conducted in New York and Paris. 

One of the drugs, a translational regulation inhibitor known as zotatifin (a product of Effector Therapeutics co-founded by UCSF scientists, including Kevan Shokat), has just been FDA-approved for a phase 1 clinical trial with $5 million in funding from the Defense Advanced Research Projects Agency, he reports. Zotatifin is currently being tested in patients with solid tumors, and results of preclinical studies showing its in vitro antiviral activity against SARS-CoV-2 were reported last spring in Nature (DOI: 10.1038/s41586-020-2286-9).   

The other drug, plitidepsin (Aplidin), approved by the Australian Regulatory Agency for the treatment of multiple myeloma, was found to be 27.5-fold more potent against SARS-CoV-2 than remdesivir, as reported earlier this year in Science (DOI: 10.1126/science.abf4058). Researchers demonstrated prophylactic treatment reduced viral replication in the lungs of mice by two orders of magnitude. 

PharmaMar has already launched a phase 3 clinical trial using plitidepsin as a treatment for patients hospitalized for management of moderate COVID-19 infection, Krogan says. The study has been approved to run in 12 countries at 27 different sites. 

Cancer drugs targeting human proteins often need to be taken for months or years, he adds. But as a treatment for acute infection by SARS-CoV-2, patients need only a short course of plitidepsin for a few days.  

The challenge now is how to sustain large-scale collaborations with scientists needing to resume work on projects put on pause while they were battling COVID, says Krogan. But he is determined not to backtrack because science moves faster when everyone is working together, and scientist trainees also seem to learn better. 

In addition to QCRG and the Host-Pathogen Map Initiative, UCSF is involved in a Cancer Cell Map Initiative looking at the molecular networks (based on protein-protein and genetic interactions) underlying cancer, he notes. It also has a Psychiatric Cell Map Initiative to elucidate the physical and genetic interaction networks associated with neuropsychiatric disorders such as autism and schizophrenia. 

Big discoveries in the future are going to come from scientific collaboration like these across disease and specialty areas, Krogan says. “There is so much overlap there we just don’t [otherwise] appreciate.”