Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses.
Author
White, Judith MSchiffer, Joshua T
Bender Ignacio, Rachel A
Xu, Shuang
Kainov, Denis
Ianevski, Aleksandr
Aittokallio, Tero
Frieman, Matthew
Olinger, Gene G
Polyak, Stephen J
Date
2021-12-21Journal
mBioPublisher
American Society for MicrobiologyType
Article
Metadata
Show full item recordAbstract
The world was unprepared for coronavirus disease 2019 (COVID-19) and remains ill-equipped for future pandemics. While unprecedented strides have been made developing vaccines and treatments for COVID-19, there remains a need for highly effective and widely available regimens for ambulatory use for novel coronaviruses and other viral pathogens. We posit that a priority is to develop pan-family drug cocktails to enhance potency, limit toxicity, and avoid drug resistance. We urge cocktail development for all viruses with pandemic potential both in the short term (<1 to 2 years) and longer term with pairs of drugs in advanced clinical testing or repurposed agents approved for other indications. While significant efforts were launched against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro and in the clinic, many studies employed solo drugs and had disappointing results. Here, we review drug combination studies against SARS-CoV-2 and other viruses and introduce a model-driven approach to assess drug pairs with the highest likelihood of clinical efficacy. Where component agents lack sufficient potency, we advocate for synergistic combinations to achieve therapeutic levels. We also discuss issues that stymied therapeutic progress against COVID-19, including testing of agents with low likelihood of efficacy late in clinical disease and lack of focus on developing virologic surrogate endpoints. There is a need to expedite efficient clinical trials testing drug combinations that could be taken at home by recently infected individuals and exposed contacts as early as possible during the next pandemic, whether caused by a coronavirus or another viral pathogen. The approach herein represents a proactive plan for global viral pandemic preparedness.Keyword
COVID-19Ebola virus
SARS-CoV-2
antiviral drugs
category A-C pathogens
countermeasures
drug synergy
early treatment
model-driven approach
pandemic preparedness
prophylaxis
viral pandemic
Identifier to cite or link to this item
http://hdl.handle.net/10713/17593ae974a485f413a2113503eed53cd6c53
10.1128/mbio.03347-21