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.

One thought on “Retooling a COVID drug to boost its effectiveness

  1. 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.

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