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Replies to post #230028 on Biotech Values
To come up with an alternative, scientists at Georgia State University and Emory University, both in Atlanta, investigated a compound named N-hydroxycytidine (NHC), which has been known for years to inhibit a broad range of RNA viruses like the flu. Previously, the researchers had shown that NHC is active against influenza; but in tests on macaques, they found the drug is not taken up well by the body, “a potential deal breaker” for human use, says Georgia State molecular virologist Richard Plemper, one of the researchers leading the new work.
The researchers tweaked NHC’s structure to create a new compound named EIDD-2801, which converts back into NHC inside the body. They then tested it in ferrets, the most widely used animal model for influenza. If the ferrets received the compound 12 hours after infection, they did not develop disease at all. Those that received it after 24 hours, when fever had started, produced less virus than control animals that received oseltamivir or no treatment at all. The fever also ended faster in treated animals, the researchers write in Science Translational Medicine.
“It’s important that they showed a reduction in symptoms in ferrets, because it gets much closer to predicting what happens in people,” says Andrew Pavia, an infectious disease expert at the University of Utah in Salt Lake City. “It’s a major step towards developing a drug for humans.”
The scientists also investigated how NHC blocks influenza by sequencing the genomes of flu viruses exposed to the compound. They found that the virus incorporates the drug into its RNA when it replicates, instead of a molecule named cytosine, leading to a cascade of mistakes that virologists call “error catastrophe”—essentially overwhelming the virus with mutations.
To test how easily flu becomes resistant to EIDD-2801, the researchers also grew the virus while keeping it exposed to sublethal doses of NHC or slowly increasing the concentration of NHC—methods that typically don’t kill the virus, but give it a chance to evolve resistance. Even though sequencing clearly shows the virus trying to resist the drug, no resistant strains developed. That bodes well, Pavia says, because oseltamivir and other older drugs all eventually fail the test.
These results point to a virus-mutagenic mechanism of NHC inhibition in CoVs and indicate a high genetic barrier to NHC resistance. Together, the data support further development of NHC for treatment of CoVs and suggest a novel mechanism of NHC interaction with the CoV replication complex that may shed light on critical aspects of replication.IMPORTANCE The emergence of coronaviruses (CoVs) into human populations from animal reservoirs has demonstrated their epidemic capability, pandemic potential, and ability to cause severe disease. However, no antivirals have been approved to treat these infections.
Here, we demonstrate the potent antiviral activity of a broad-spectrum ribonucleoside analogue, ß-d-N 4-hydroxycytidine (NHC), against two divergent CoVs. Viral proofreading activity does not markedly impact sensitivity to NHC inhibition, suggesting a novel interaction between a nucleoside analogue inhibitor and the CoV replicase. Further, passage in the presence of NHC generates only low-level resistance, likely due to the accumulation of multiple potentially deleterious transition mutations. Together, these data support a mutagenic mechanism of inhibition by NHC and further support the development of NHC for treatment of CoV infections.
Headquartered in Miami, Florida, Ridgeback Biotherapeutics is a privately held, majority woman owned biotechnology company focused on orphan and infectious diseases. To date, all funding for Ridgeback Biotherapeutics has originated from Wayne and Wendy Holman; two individuals committed to investing in and supporting technologies that will make the world a better place. The team at Ridgeback is dedicated to working toward finding life-saving and life changing solutions for patients and diseases that need champions.
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