Rethinking Remdesivir

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Remdesivir is an antiviral drug originally discovered as part of a program to develop antiviral agents with activity against new emerging viruses. During the first months of the COVID-19 pandemic, it was tested as a potential therapy and found to significantly reduce the recovery time of COVID-19 hospital patients. The Food and Drug Administration approved its use in October 2020 and it remains the only antiviral approved by the FDA for the treatment of SARS-CoV-2 infection.

Currently, remdesivir must be administered intravenously, a process that restricts its use to hospital patients with relatively severe or advanced cases of COVID-19. The FDA has approved the use of remdesivir only for adults and children 12 years of age and older.

In a new article, published in the July 26, 2021 online issue of

Antimicrobial agents and chemotherapy, researchers at the University of California, San Diego School of Medicine describe cell and animal studies that demonstrate how lipid changes in the remdesivir nucleoside can improve drug delivery, efficacy, and toxicity compared to remdesivir.

“Although vaccine development had a major impact on the epidemic, COVID-19 continued to spread and cause disease – particularly among the unvaccinated,” said co-lead author Robert T. Schooley , MD, professor of medicine at UC San Diego School. of Medicine. “With the evolution of more transmissible viral variants, revolutionary cases of COVID are being observed, some of which can be severe in people with underlying diseases. The need for effective and well-tolerated antiviral drugs that can be granted to high patents risk of serious disease in the early stages of the disease remains high. “

Lead author Karl Hostetler, MD, professor of medicine at UC San Diego School of Medicine, and colleagues synthesized three new lipid prodrugs, which combine a therapeutic agent (in this case, the nucleoside remdesivir) with the one of the many types of lipid phosphates. The resulting conjugate molecule uses new pathways to enter cells: the lipid phosphate part that carries the drug.

The lipid phosphate prodrugs of the remdesivir nucleoside can be taken orally, remaining intact and bioactive in the body after absorption through the digestive system.

“COVID-19 is a two-stage disease,” Schooley said. “Rapid viral growth occurs soon after infection and can trigger a misdirected immune response that leads to ‘inflammatory’ pneumonia in those who are not doing well. To be most effective, antiviral therapy should be given at the onset of the disease before the inflammatory phase of the disease leads to hospitalization. These compounds are designed to be taken orally, rapidly absorbed from the gastrointestinal tract, and largely bypassed the liver where most of the toxicity of remdesivir is observed.

To become active, remdesivir requires modification by several enzymes. This complicated metabolism likely contributes to varying antiviral activity and toxicity in different cell types. For example, remdesivir works well in lung cells, but is less effective in other organs and is relatively more toxic in hepatocytes (liver cells), which limits the amount of medicine that can be given to patients. In comparison, the lipid prodrugs described in the new article are activated by a simple single enzymatic reaction and exhibit consistently potent antiviral activity and minimal toxicity to many cell types.

“An optimal antiviral for the treatment of SARS-CoV-2, and potentially other emerging viral infections, would be equally effective in any type of cell that might become infected,” said co-lead author Aaron F. Carlin, MD, assistant professor of medicine and infectious disease specialist at UC San Diego Health. “The metabolism of remdesivir is complex, which can lead to variable antiviral activity in different types of cells. In contrast, these lipid-modified compounds are designed to be activated in a simple and uniform manner, leading to consistent antiviral activity on many cell types. “

Researchers evaluated lipid prodrugs in various animal and human cell types and found that lipid prodrugs uniformly inhibited SARS-CoV-2 RNA replication across cell types. They were well tolerated by hamsters, with drug levels remaining stable and persistent, a problem with current remdesivir treatments.

“We believe that lipid prodrugs of this type after further development can reduce the severity of COVID-19 infections and reduce hospitalizations,” Hostetler said.

Co-authors include: James R. Beadle, Nadejda Valiaeva, Xing-Quan Zhang, Alex E. Clark, Rachel E. McMillan, Jialei Xie, Aaron F. Garretson, Victoria I. Smith, and Joyce Murphy, all at UC San Diego; Sandra L. Leibel, UC San Diego and Sanford Consortium for Regenerative Medicine; and Rachael N. McVicar, Sanford Consortium for Regenerative Medicine and Sanford Burnham Prebys Medical Discovery Institute.

Funding for this research comes, in part, from the National Institute of Allergy and Infectious Disease (grant RO1 AI131424), the San Diego Center for AIDS Research, the National Institutes of Health (K08 AI130381), the Burroughs Wellcome Fund and the California Institute for Regenerative Medicine (DISC2COVID19-12022).

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