A multi-institutional group led by the University of California at San Francisco’s Quantitative Biosciences Institute (QBI) has identified more than 200 host proteins that interacted with SARS-CoV-2 viral proteins during infection, creating “a blueprint of how SARS-CoV-2 hijacks human cells,” QBI Director Nevan Krogan told reporters.

They then used that blueprint to identify 10 drugs, some FDA approved and some in clinical trials, that were able to inhibit viral growth in cell culture assays, marking them for further study as potential antivirals. The work also identified one compound, dextromethorphan, that appeared to facilitate viral growth.

The evidence for both antiviral and proviral effects is so far limited to cell cultures of African green monkey-derived Vero E6 cells.

“Should we be careful” in drawing conclusions? “Yes, we should be careful. These are in vitro results,” Brian Shoichet told reporters at a press conference describing the study, which was published in the April 30, 2020, online issue of Nature.

“We need more information, we need more data, we need clinical trials,” added Krogan.

But in focusing on repurposing drugs, the study has identified compounds that can be fast-tracked for clinical development against SARS-CoV-2, since “most of an IND is independent of disease,” Steve Worland told BioWorld.

Worland is president and CEO of Effector Therapeutics Inc., whose experimental cancer drug, zotatifin, was one of two selective protein translation initiation inhibitors identified in the Nature study as having in vitro activity against SARS-CoV-2, along with approved multiple myeloma drug Aplidin (ternatin-4/plitidepsin, Pharmamar SA).

Inhibiting the initiation of translation stops coronaviruses in their tracks, Worland explained, because coronaviruses and other positive-strand RNA viruses are “totally dependent” on the host cell machinery for replicating.

“The virus carries into the cell one single messenger RNA molecule, and the whole thing starts from there,” and when that messenger RNA molecule is translated with the help of host proteins, including zotatifin’s target eIF4A, the virus “can’t get the ball rolling, [and] nothing ever happens.”

Zotatifin is currently in a phase I/II trial in patients with a targeted set of solid tumors. At the American Association for Cancer Research virtual annual meeting held earlier this week, Effector’s Peggy Thompson presented data showing that the drug inhibited a diverse set of receptor tyrosine kinase-driven tumors, including KRAS-mutated tumors. The company is now working toward a phase I trial in COVID-19 patients as well.

“It’s been a remarkable six or eight weeks,” Worland said.

Host-directed therapies

The other major host factor identified in the work by the QBI team were the Sigma receptors, SigmaR1 and SigmaR2. A structurally diverse group of Sigma receptor modulators, including the antihistamines cloperastine and clemastine, the antipsychotics haloperidol and melperone, and the antimalarial hydroxychloroquine, killed SARS-CoV-2.

Hydroxychloroquine’s presence on the list is a testament to both the pitfalls and the promise of in vitro studies. After earlier research had suggested the antimalarial drug might work against SARS-CoV-2, clinical studies showed serious cardiac toxicities of the drug.

However, it appears that hydroxychloroquine toxicity is not due to SigmaR binding, but rather to off-target effects on an ion channel, the hERG channel. Other compounds in the screen such as clemastine did not share hydroxychloroquine’s affinity for hERG, suggesting they might be a less toxic means to the same end.

Toxicity is, in general, a concern for host-directed therapies compared to direct-acting antiviral drugs.

“Targeting host factors has been considered a little bit risky because they have normal function,” Alfredo Garcia-Sastre, Nature co-author and director of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine, told reporters. But, he noted, by the time an antiviral is needed, a virus has already hijacked that cell.

“A normal cell and a virus-infected cell, they are very different things,” Sastre said. “We can take this to our advantage to target things that have made the cell different.”

Kevan Shokat, chair of the department of molecular and cellular pharmacology at UCSF and another co-author on the Nature publication, added that toxicity concerns are also of a different nature for drugs that are taken for a brief time period.

While a chronic medication has to be “squeaky clean” in terms of its side-effect profile, he said, the risk-benefit calculation is different for a drug that is used for a week or two.

And though toxicity is a greater concern, host-directed therapies also offer the hope of broad-spectrum therapies – something that could help control not just the COVID-19 pandemic, but future outbreaks as well.

“If we can come up with a treatment that works for COVID-19, it could potentially work for COVID-22, COVID-24 and so forth,” Krogan said.

And Shokat added that when looking at the interactions of other RNA viruses, such as Ebola, Zika or HIV, “we do see these commonalities, we see these same proteins come up again and again.”

No Comments