Can COVID-19 Reboot Drug Repurposing?

It seems like a slam dunk. Why not repurpose already approved or well-studied drug candidates for conditions where treatments are desperately needed? Wouldn’t that be an easy way to speed up drug development?

There are multiple examples where that has been very successful (see Stunning Success Stories). But there are also huge hurdles. “Who, besides the drug’s owners, can afford to sponsor such studies?” has been one of the most longstanding issues that has hampered many such efforts. But now there is an important new question, “Can recent technological advances, particularly in genomics, make repurposing more practical and efficient?”

The COVID-19 pandemic brought this into sharper focus as many scrambled to quickly find treatments for this new disease. The suddenness, size, and impact of the pandemic caught everyone off guard. COVID-19 has a much higher infection rate compared to earlier coronaviruses.

“This has made drug repurposing especially important,” said Harish Vashisth, PhD, professor of chemical engineering at the University of New Hampshire.  “We just don’t have the time to go through the conventional drug development process.”

By March 2020, there were already 24 trials listed on the clinicaltrials.gov website that involved drug repositioning for this new viral disease, according to a report by the Pan American Health Organization and the World Health Organization. These included more than 20 medicines, including human immunoglobulin, interferons, chloroquine, hydroxychloroquine, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, methylprednisolone, and bevacizumab.

Notably, former President Donald Trump received anti-viral remdesivir (Regeneron’s Veklury), as well as an experimental antibody treatment and steroid, when he developed COVID-19 in early October 2020, while still in office. Remdesivir was originally developed for treatment of other infections, including hepatitis C and Ebola. Shortly after Trump received it, the drug went on to become the first treatment specifically approved for COVID-19 in late October.

Since then, there has been a wave of research to find any known compounds that might be useful against the disease. There have also been scientific advances, as described below, that should make it possible to fast-track drug repurposing. One recent report suggests that using genomics approaches, researchers have identified more than 200 potential SARS-CoV-2 targeting molecules. (Chen et al. iScience, Oct. 21, 2022).

“The number of resources for viral research has increased exponentially,” said Vashisth. “There is an explosion of work worldwide.”

In addition, there are more public tools to support this effort. For example, a COVID-19 OpenData Portal was established by the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS). The portal data was developed by using SARS-CoV-2-related assays to screen over 10,000 compounds, including the NCATS Pharmaceutical Collection of nearly 3,000 approved drugs, for their activity against the virus. The Portal includes information on assays, protocols for using them, drug targets, mechanisms of drug action, and screening assay data.

Guided by gene expression signatures

Some groups are already using their own and public data to forge ahead.

Bin Chen, PhD., and colleagues at Michigan State University use a data-driven approach with gene expression profiles of disease and cellular response to chemical compounds, both of which have proliferated in public databases. The central idea is that certain antiviral drugs can suppress over-expressed genes and activate repressed genes, regardless of drug mechanisms and biological systems involved.

The team recently evaluated hundreds of signatures derived from 1,700 published transcriptomic profiles of SARS/MERS/SARS-CoV-2 infection from cell lines, mice, organoids, and actual patient samples (Chen et al. iScience, Oct. 21, 2022). Chen and his co-authors point out that this approach addresses a central problem: “The molecular manifestations of host cells responding to SARS-CoV-2 and its evolving variants of infection are vastly different across the studied models and conditions.”

Some of the signatures they found could be reversed by known anti-SARS-CoV-2 inhibitors. The team used those signatures to find potential inhibitors of new variants. One drug, IMD-0354, could reverse the signatures for SARS-CoV-2 and its five variants. This compound stimulated type I interferon antiviral response, inhibited viral entry, and down-regulated hijacked proteins.

“Most people have focused on the viral protein,” Chen said. “We are focused on the host response to variants and finding gene expression signatures of response.” This technique, he notes, allows them to look at several variants at once.

Chen and his colleagues have applied this same technique already in repurposing drugs for Alzheimer’s, brain cancer, and other conditions.

They described some of their cancer work in an earlier paper (Chen et al. Nature, Dec. 2020). They also developed Open Cancer TherApeutic Discovery (OCTAD; http://octad.org) for virtually screening compounds targeting subsets of cancer patients using gene expression features. The database includes 19,127 patient tissue samples covering more than 50 cancer types and expression profiles for 12,442 distinct compounds.

Targeting viral proteins

Vashisth and his colleagues are focused on a key SARS-CoV-2 protease enzyme called Mpro, which is essential for the virus’s replication. It cuts up long chains of polypeptide proteins of the virus into smaller component proteins. These smaller segments can fold and mature to form new virus particles.

Of the SARS-CoV-2 proteins, Mpro is considered a favored therapeutic target due to its high sequence conservation with proteases of other coronaviruses.

“Many antibody molecules actually bind to the virus to block it’s entry into the cell. We were interested in stopping replication once it was in the cell,” Vashisth said.

They researched the inhibiting properties of thiadiazolidinones, or TDZDs, which are already being studied as a potential treatment for neurological disorders such as Parkinson’s Disease.

“We were already working on a family of proteins that we believed targeted cysteine amino acids. And COVID-19 is also dependent on that,” said Vashisth. His group looked at a specific TDZD compound, known as CCG-50014. Using computational models combined with laboratory experiments, the researchers were able to determine that this compound did inhibit Mpro (Vashisth et al. Proteins, Structure, Function, and Bioinformatics, May 2022).

They are continuing this work. “We now have a family of compounds that we are looking at, and they target other proteins as well,” he said.

Fine-tuning a scaffold and more Screening is just the starting point for Robert Davey, PhD, a professor of microbiology at Boston University. “This way you get to start with a drug whose pharmacology we have a good understanding of,” he said. “Most of the time, we find that clinically used drugs have been so well-refined by pharma, as they should be, that they are specifically-suited for the indication they are already used for.”

Usually, these drugs were tested in low doses, which makes them impractical to use for other indications. The group saves time and effort by using these hits as scaffolds they build upon to create a compound that can be used in a new disease but at a safe dose.

“I’ve been testing this idea out for about seven years with some success,” Davey said. “We build on new parts that tune the scaffold to the new indication, and then recheck how the new drug is working along the way.”

They use the open-access Broad Institute Repurposing Hub, which contains more than 6,000 compounds, many of which have been FDA approved. And Davey’ lab is teamed with that of  Albert-László Barabási’s group at Northeastern University. “They are one of the best groups in the field of cell protein network analysis, and they have helped to drive our analysis of mechanism of action,” he said.

He points to a drug candidate called amodiaquine, which is used for the therapy of malaria. “We were able to improve its ability to target Ebola by ten times,” he said.

In a recent study, Davey’s team evaluated 6,710 clinical and preclinical compounds targeting 2,183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. They computationally integrated relationships between small molecule structure, dose-response antiviral activity, host target, and cell interactome generated cellular networks implicated in infection. The team found 389 small molecules with relevant activity (Davey et al. iScience, Sept. 2022).

There are plenty of other research groups and companies pursuing repurposing, especially in COVID-19.

• A laboratory led by Toshinori Endo, PhD, at Hokkaido University, recently published on using machine learning and gene expression for repurposing. They examined disease-specific gene expression data for inclusion body myositis, polymyositis, and dermatomyositis (DM), to identify small-molecule compounds that reversed these expression patterns (OMICS a Journal of Integrative Biology. June 13. 2022). They found 20 drugs, such as BMS-387032, phorbol-12-myristate-13-acetate, mitoxantrone, alvocidib, and vorinostat as candidates for repurposing.

• A SARS-CoV-2-humanprotein-protein interactome was created by a group led by Haiyuan Yu of the Center for Proteomics at Cornell University.  They used high-throughput yeast two-hybrid experiments and mass spectrometry to generate a comprehensive SARS-CoV-2–human protein–protein interactome network consisting of 739 high-confidence binary and co-complex interactions, validating 218 known SARS-CoV-2 host factors and revealing 361 novel ones. They found 19 potential pathobiology and host therapeutic targets (Yu et al, Nature Biotechnology, Oct. 10, 2022).

• Harald Schmidt PhD, of Maastricht University is leading efforts to understand molecular causes of disease and how they interact. “It turns out there are several genes involved in forming dysfunctional signaling,” he explained. “To correct such networks you need more than one drug,” His team is now working on “network pharmacology” (Schmidt et al. Trends in Pharmacological Sciences. Dec. 2021.) His group aims to apply this to drug repurposing among other uses.

• Artificial Intelligence start-up Healx is a Cambridge University spinout focused on repurposing existing drugs into rare disease treatments. Healx’s effort is centered around its rare disease database HealNet, which has mapped more than 1 billion unique disease, patient and drug interactions.

HealNet was built and is maintained using machine learning methods applied to a wide range of data types from both publicly available and exclusive sources including scientific literature, patents, clinical trials, disease symptoms, drug targets, multi-omic data and underlying chemical structures.

Still high hurdles

So how is that slam dunk looking?

The fruits of all these new efforts have been few at this point, but the interest in repurposing remains high.

“I don’t think that COVID–19 research has invigorated the field,”  said Schmidt. “It has spurred a lot of drug repurposing projects, gazillions of predictions, but none made it to the patients.”

He still has plenty of optimism about the field as a whole. “We will soon have all the drugs we need,” he said. “We just need to repurpose them cleverly.” He points out that based on structural biology, there are only about 1,200 drug binding sites, which makes it a reasonable goal.

There are still plenty of hurdles, including basic science issues that have dogged drug development for years. As Leslie Gordon, medical director of the Progeria Research Foundation (PRF) points out, “There is still no way to know if a drug that works in a mouse model or on cells in a laboratory dish will translate into clinical benefits for children.”

Chen notes that when his team did find a drug that could possibly be repurposed for COVID-19, its maker wouldn’t even respond when his team tried to contact them. Chen and his colleagues have moved on though, “We have synthesized a number of analogues with even better properties,” he said.

Vashisth points out that the issue of side effects can be also be tricky, “Drugs are specifically approved for certain diseases, and in each one there is a particular matrix of what benefits are gained versus which side effects are tolerable.”

Davey agrees. “When we try to repurpose these drugs, we need at least 10 or 100X higher doses to get efficacy which greatly increases the chances of side effects,” he said. That’s why he prefers to use approved or drug candidates as a starting point for further refinement.

He said that several studies came out early in the pandemic that identified drugs that inhibited SARS-CoV infection, but were only effective at doses well above their approved clinical doses.  “This was the case for compounds such as chloroquine and ivermectin,” he said, “which do block infection in cell models, but only when used well above the safe amounts.”

The PRF scored a victory in repurposing through a combination of focus, outreach to researchers, luck, aggressive fundraising, and cooperation of drug developers. Remarkably, the group went from gene discovery to their first clinical trial in about four years – a testament to the potential of repurposing. (See Stunning Success Stories).

Although they are also looking at mRNA, gene therapy, and CRISPR, PRF intends to continue to pursue repurposing. “We recently held an international scientific meeting and there was a lot of exciting data shared on drugs that should be explored for repurposing in Progeria,” Gordon said. “This included anti-aging, anti-inflammatory, and other types of drugs that are either commercially available or in trials for other disease populations.”

Gordon knows better than most what’s at stake here. She is not only a physician but also a co-founder of PRF with her husband Scott Berns, MD, M.P.H. Her son Sam had the condition and was in two of the clinical trials for the drug, lonafarnib, which PRF successfully repurposed. Sam was an active advocate for the disease, becoming famous in part for a documentary about him (Life According to Sam) and a TEDx talk he gave that went viral. He died in 2014 at the age of 17.

Malorye Branca is a freelance science writer based in Acton, MA.