Newswise — We've all had a quick lesson in repurposing drugs recently, thanks to almost daily news on efforts to find existing medicines for treating COVID-19 in the early stages of the pandemic. The Wyss Institute team at Harvard University joined the fight in spring 2020, using new computational drug repurposing methods to tackle the COVID-19 challenge. This early effort led to the surprising forecast that certain types of statins (commonly prescribed cholesterol-lowering drugs) may guard patients against SARS-CoV-2 infection. Other researchers studying COVID-19 published a flurry of clinical studies, with some finding that statins reduce mortality in COVID-19 patients, while others found no effect. However, these studies did not differentiate between various statin drugs.
Presently, the Wyss squad, in conjunction with colleagues at Stanford University and University of California, San Francisco (UCSF), have validated that only a portion of these drugs, specifically simvastatin (Zocor®) and atorvastatin (Lipitor®), can decrease the risk of mortality in COVID-19 patients. The team further proved that simvastatin vigorously hindered the virus and lowered the generation of inflammatory cytokines, whereas other statins did not.
Co-first author Megan Sperry, Ph.D., a Postdoctoral Fellow at the Wyss Institute, stated, "This study sheds light on the fact that the biomedical field lacks a complete understanding of the mechanisms of action of drugs that are widely prescribed. There's a significant amount of research that can be carried out to explore the various functions of drugs and identify new applications for existing medications." The research has been published in PLOS Computational Biology.
Predicting potency
For some time, statin research has recognized that while all statins reduce cholesterol by targeting an enzyme called HMGCR, different drugs appear to have different effects on patients. However, there was a lack of drive (and funding) to uncover exactly what those effects were until the advent of COVID-19. In an effort to curb the pandemic, the United States' Defense Advanced Research Projects Agency (DARPA) granted the Wyss Institute $16 million in spring 2020 to identify and test FDA-approved drugs that could be repurposed to prevent or treat COVID-19. Using a computational tool called Network Model for Causality-Aware Discovery (NeMoCAD), developed with previous DARPA funding, the Wyss team assessed statins among other compounds.
Using a network analysis-based algorithm, NeMoCAD predicts drugs that can reverse a diseased gene network to a healthy gene network. The Wyss team applied this tool to predict drugs that could target gene networks found in tissue samples from COVID-19 patients versus healthy patients. NeMoCAD identified drugs that could convert the diseased gene networks to healthy gene networks, and these drugs were then subjected to further testing using cell culture, human Organ Chips, and animal models.
The Wyss team utilized NeMoCAD to evaluate 2,436 drugs and found that a subset of statin drugs was predicted to restore a COVID-19 state to a healthy state. These statins included simvastatin, atorvastatin, pravastatin (Pravachol®), lovastatin (Altoprev®), and fluvastatin (Lescol®). However, only simvastatin and atorvastatin were ranked as highly protective, while the others showed a much weaker predicted effect, despite all statins sharing a common, well-defined mechanism of action against their target.
Based on these observations and in vitro experimental data, the Wyss team concluded that statins had varying effects against SARS-CoV-2, suggesting that a more detailed investigation was necessary to identify which individual drugs could potentially be used to treat COVID-19.
However, other scientists studying COVID-19 worldwide began to publish research indicating that patients taking statins appeared to be shielded from the severe effects of SARS-CoV-2 infection. Nevertheless, these studies had classified the entire category of "statins" as effective, whereas the Wyss team knew from their NeMoCAD studies that it was highly probable that only a subset of statins were genuinely protective.
Co-senior author Richard Novak, Ph.D. contacted teams at Stanford University and UCSF that had released research on statins, suggesting that they team up with the Wyss scientists to explore the distinct effects of specific statins within their dataset. Novak identified two characteristics of this patient population that made it especially ideal for additional research: individuals taking statins had comparable risk factor profiles, such as high cholesterol, and doctors prescribed statins interchangeably, which effectively randomized which patients had received which statin.
One drug comes out on top
The collaborative study found that only simvastatin and atorvastatin were associated with reduced mortality risk in COVID-19 patients among the group of more than 4,000 individuals who were taking statins when infected with SARS-CoV-2. These findings confirm that not all statins have the same impact on the body, despite their similar chemical structure.
These in vitro studies suggest that simvastatin may have a potent inhibitory effect on SARS-CoV-2 and related coronaviruses, as well as the ability to reduce inflammatory cytokines without causing toxicity. The results also support the predictive power of NeMoCAD in identifying potential drug candidates for COVID-19 treatment.
"Thanks to the vast clinical data and multidisciplinary capabilities of the Wyss Institute, we delved deeper than previous studies, utilizing diverse models and analyses to determine how various statins impact infection rates and the immune response. Ultimately, this study showcases how we can systematically combine tools in the lab to improve drug understanding and expedite repurposing for pandemics or other clinical demands." commented Novak, the former Lead Staff Engineer at Wyss Institute. He is currently the CEO and co-founder of Unravel Biosciences.
The Wyss group is persisting in utilizing this methodology to unearth drugs that can be repurposed for diverse applications, including inducing biological "suspended animation" in tissues or entire organisms to extend the duration for which they can subsist before receiving therapy.
"Medications are typically approved for singular purposes in the human body, yet the presence of commonly referred to 'side effects' for almost all drugs strongly implies that these compounds impact multiple biological systems," said Donald Ingber, M.D., Ph.D., corresponding author and leader of the DARPA COVID-19 program, and Founding Director of the Wyss Institute. He is also the Judah Folkman Professor of Vascular Biology at Boston Children's Hospital and Harvard Medical School, and the Hansjörg Wyss Professor of Bioinspired Engineering at Harvard John A. Paulson School of Engineering and Applied Sciences. "Research such as this one provides a clear demonstration that the off-target effects of FDA-approved drugs can and should be characterized and utilized in practical ways to tackle pressing health issues in humans."
The paper also includes contributions from Tomiko Oskotsky and Marina Sirota as co-first and co-senior authors, respectively, along with Idit Kosti and Brian Le from UCSF, and Ivana Marić, Ronald Wong, and David Stevenson from Stanford University. Other authors include current Wyss Institute members Viktor Horvath, Pranav Prabhala, Girija Goyal, Ken Carlson, Melissa Rodas, and Brooke Furlong, as well as former Wyss Institute members Shruti Kaushal, Takako Takeda, Rani Powers, and Mercy Soong. The University of Maryland's James Logue, Holly Hammond, and Matthew Frieman also contributed to the study.
The research discussed in the article received funding from various sources, including the Defense Advanced Research Projects Agency (DARPA), the Wyss Institute for Biologically Inspired Engineering at Harvard University, the Christopher Hess Research Fund, the University of California, San Francisco (UCSF) Program for Breakthrough Biomedical Research, the Medical Scientist Training Program, and the National Institutes of Health (NIH).
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