The origin story: From Hepatitis C to Ebola investigation
Before becoming widely known for COVID-19, remdesivir (Veklury) was initially developed by Gilead Sciences as a treatment for hepatitis C, though it was found to be ineffective against both hepatitis C and respiratory syncytial virus (RSV) in early research. This led to investigations into its potential against other dangerous RNA viruses, particularly the Ebola virus (EBOV).
Promising preclinical studies in cell cultures and animal models demonstrated remdesivir's ability to suppress EBOV replication. Consequently, remdesivir was included in a clinical trial during the 2018 Kivu Ebola outbreak. However, a 2019 analysis showed remdesivir was less effective in reducing mortality compared to two antibody-based therapies, resulting in its removal from the trial.
Remdesivir's broad-spectrum antiviral activity
Remdesivir acts as a nucleotide analogue, interfering with viral RNA-dependent RNA polymerase (RdRp), an enzyme vital for the replication of many RNA viruses. This mechanism provides broad-spectrum activity beyond filoviruses like Ebola, as demonstrated in numerous in vitro and preclinical studies. A full list of viruses remdesivir is active against can be found on {Link: PubMed Central https://pmc.ncbi.nlm.nih.gov/articles/PMC7836944/}. Preclinical animal studies have also supported remdesivir's potential against MERS-CoV and Nipah virus. Studies in rhesus macaques infected with MERS-CoV showed reduced lung viral loads and improved clinical signs with prophylactic remdesivir. For Nipah virus, treatment with remdesivir led to 100% survival in African green monkeys with lethal infections.
Comparative applications of remdesivir outside of COVID-19
Remdesivir has been evaluated against several viral pathogens. The table below compares its development path for Ebola, MERS, and SARS:
| Feature | Ebola Virus (EBOV) | MERS-CoV | SARS-CoV |
|---|---|---|---|
| Development Phase | Clinical Trial (Phase 2/3) | Preclinical and Animal Studies | Preclinical and Animal Studies |
| Trial Outcome | Inferior to antibody-based therapies; arm terminated | Promising results in animal models | Effective in mouse models |
| Efficacy | Reduced viral RNA but less impact on mortality than monoclonal antibodies | Reduced viral load and lung damage | Decreased pulmonary viral load and improved respiratory function |
| Role | Investigational therapy, later superseded | Potential therapeutic option demonstrated in preclinical settings | Potential therapeutic option demonstrated in preclinical settings |
The delayed chain termination mechanism
Remdesivir is a phosphoramidate prodrug that converts to an active nucleoside triphosphate inside cells. This active form inhibits viral RdRp by acting as a 'delayed chain terminator'. Unlike typical chain terminators, it allows a few more nucleotides to be added before stopping RNA synthesis, making it less susceptible to the virus's proofreading mechanisms.
Remdesivir selectively targets viral replication due to human polymerases having higher selectivity for natural nucleosides. This selective inhibition contributes to its broad-spectrum potential against many RNA viruses.
Conclusion: A broad-spectrum antiviral with a diverse history
Remdesivir's history illustrates the dynamic nature of antiviral drug development. Its path began with a different target and included significant research against serious viral threats like Ebola, SARS, and MERS. Although other treatments proved more effective for Ebola in clinical trials, the preclinical data on remdesivir's broad-spectrum efficacy was crucial during the COVID-19 pandemic. Understanding what is remdesivir used for other than COVID-19? highlights its origins as a potential pan-antiviral with preclinical activity against various RNA viruses, cementing its role in viral disease research and pandemic preparedness. Further details on its development, including its early development for hepatitis C, Ebola trials, preclinical efficacy against various RNA viruses, mechanism of action, and repurposing for COVID-19, are available in scientific publications such as {Link: PubMed Central https://pmc.ncbi.nlm.nih.gov/articles/PMC7836944/}.
