Retooling a COVID drug to boost its effectiveness

Coronavirus particles, illustration.

When the COVID-19 pandemic broke out scientists scrambled to find existing medications that might help counter the life-threatening elements of the virus. One of the first medications that showed real promise was remdesivir. It’s an anti-viral drug that was originally developed to target novel, emerging viruses, viruses like COVID19. It was approved for use by the Food and Drug Administration (FDA) in October 2020.

Remdesivir showed real benefits for some patients, reducing recovery time for those in the hospital, but it also had problems. It had to be delivered intravenously, meaning it could only be used in a hospital setting. And it was toxic if given in too high a dose.

In a new study – partially funded by CIRM (DISC2 COVID19-12022 $228,229) – researchers at the University of California San Diego (UCSD) found that by modifying some aspects of remdesivir they were able to make it easier to take and less toxic.

In a news release about the work Dr. Robert Schooley, a first author on the study, says we still need medications like this.

“Although vaccine development has had a major impact on the epidemic, COVID-19 has continued to spread and cause disease — especially among the unvaccinated. With the evolution of more transmissible viral variants, breakthrough cases of COVID are being seen, some of which can be severe in those with underlying conditions. The need for effective, well-tolerated antiviral drugs that can be given to patents at high risk for severe disease at early stages of the illness remains high.”

To be effective remdesivir must be activated by several enzymes in the body. It’s a complex process and explains why the drug is beneficial for some areas, such as the lung, but can be toxic to other areas, such as the liver. So, the researchers set out to overcome those problems.

The team created what are called lipid prodrugs, these are compounds that do not dissolve in water and are used to improve how a drug interacts with cells or other elements; they are often used to reduce the bad side effects of a medication. By inserting a modified form of remdesivir into this lipid prodrug, and then attaching it to an enzyme called a lipid-phosphate (which acts as a delivery system, bringing along the remdesivir prodrug combo), they were able to create an oral form of remdesivir.

Dr. Aaron Carlin, a co-first author of the study, says they were trying to create a hybrid version of the medication that would work equally well regardless of the tissue it interacted with.

“The metabolism of remdesivir is complex, which may lead to variable antiviral activity in different cell types. In contrast, these lipid-modified compounds are designed to be activated in a simple uniform manner leading to consistent antiviral activity across many cell types.”

When they tested the lipid prodrugs in animal models and human cells they found they were effective against COVID-19 in different cell types, including the liver. They are now working on further developing and testing the lipid prodrug to make sure it’s safe for people and that it can live up to their hopes of reducing the severity of COVID-19 infections and speed up recovery.

The study is published in the journal Antimicrobial Agents and Chemotherapy.