When COVID-19 emerged, scientists worldwide raced to identify treatments that could reduce severe illness and save lives.
One of the first antiviral drugs to show real promise was remdesivir. The FDA approved the treatment in October 2020 after studies showed it could help some hospitalized patients recover more quickly.
However, remdesivir has important limitations.
Doctors must administer the drug intravenously, which restricts its use to healthcare settings. The medication can also cause toxic side effects at high doses.
Now, researchers at the University of California, San Diego (UC San Diego) have developed a modified version of remdesivir that may overcome some of those challenges.
The study received partial support from CIRM through a COVID-19 research award.
Improving an Important COVID-19 Antiviral
Vaccines have dramatically reduced the impact of COVID-19. However, effective antiviral medications remain important.
Some people cannot receive vaccines. Others remain vulnerable because of age, underlying conditions, or weakened immune systems.
New variants can also increase the need for additional treatment options.
“We still need effective antiviral drugs that can be given early in infection,” said study co-author Dr. Robert Schooley.
Researchers believe oral medications could play an important role because patients can take them outside the hospital.
Designing a Safer, Oral Version of Remdesivir
Remdesivir works only after several enzymes in the body convert it into an active form.
That activation process is complex and varies across different tissues.
As a result, the drug can work well in some organs while causing unwanted effects in others, particularly the liver.
To address those limitations, the UC San Diego team developed modified compounds known as lipid prodrugs.
Lipid prodrugs change how medications enter cells and move through the body. Researchers often use them to improve drug delivery and reduce side effects.
The team combined a modified version of remdesivir with a lipid-based delivery system.
This approach created a form of the drug that patients could potentially take by mouth.
Consistent Activity Across Different Tissues
The researchers designed the new compounds to activate through a simpler biological pathway.
Dr. Aaron Carlin, a co-first author of the study, said the goal was to create a treatment that performs consistently across different tissues.
“The metabolism of remdesivir is complex, which may lead to variable antiviral activity in different cell types,” Carlin said.
The new lipid-modified compounds activate more uniformly, which could produce more consistent antiviral effects throughout the body.
That consistency may also help improve safety.
Encouraging Early Results
The researchers tested the new compounds in human cells and animal models.
The modified drug successfully blocked SARS-CoV-2 infection across several cell types, including liver cells.
Those findings suggest the approach may reduce some of the safety concerns associated with traditional remdesivir while maintaining antiviral activity.
The results also support the possibility of an oral treatment that patients could take earlier in the course of infection.
Earlier intervention often improves outcomes for viral diseases.
Looking Ahead
The work remains in the preclinical stage.
Researchers must complete additional studies to confirm safety and determine whether the therapy performs as expected in people.
If future testing proves successful, the modified drug could offer several advantages over traditional remdesivir:
- Oral administration instead of intravenous infusion.
- More consistent activity across different tissues.
- Reduced toxicity.
- Earlier treatment outside the hospital.
The study demonstrates how researchers continue to refine existing therapies and build on lessons learned during the pandemic.
While vaccines remain a critical defense against COVID-19, improved antiviral medications could provide another valuable tool for protecting vulnerable patients and reducing severe disease.
The findings were published in the journal Antimicrobial Agents and Chemotherapy.
Most of the RNA viruses depend on RNA-dependent RNA polymerase (RdRp) enzyme complex for genomic replication. However, a class of drugs known as nucleoside analogues has been used to inhibit infectious viruses from replication. For instance, remdesivir is a adenosine triphosphate analog with broad antiviral activities had been widely used to treat patients infected with Covid-19. Remdesivir is effective to induce non-obligate chain terminator of RdRp from SARS-CoV-2. Remdesivir is a phosphoramidite prodrug of a 1′-Cyano-substituted adenosine nucleotide analogue which compete with ATP for incorporation into newly synthesis viral RNA corresponding to RdRp complex. Most of current Covid-19 variants are highly infectious and contagious. Viruses with high replication rate tend to develop high viral loads in human body and eventually cause severe illnesses and fatality. Remdesivir had been used intravenous to patient infected with Covid-19. The high delivery rate of drugs to the tissues and organs of infected patients can efficiently block the viruses from spreading.
In compare to oral administration of remdesivir, the medication takes time to reach out to digestive tract for breaking down before absorbing, distributing and metabolized in human body. This medication route is widely welcome to patient treated at home with early infection of Covid-19 or mild symptoms. Current investigation of new medicine by inserting a modified form of remdesivir and coupling to enzyme lipid phosphate to create a hybrid version. The analysis of stability of new medicine to digestive enzymes and toxicology of metabolic byproducts to tissues and organs are paramount to maintain high levels of safety and efficacy of medicine to patient’s lives and health. The iPSCc technology to develop variety of human tissue types provide important tools to analyze safety and efficacy of drugs. Results of those partially preliminary clinical investigation may reveal important clues of mechanism of interaction between cell and metabolites of drug.