QU AND QBRI EXPLORE THE POSSIBILITY OF REPURPOSING ANTITUMOR DRUGS FOR COVID-19 TREATMENT

With COVID-19 continuing to wreak havoc across the globe, the global death toll is now over one million. A number that seemed like an exaggeration back when the pandemic started will soon become a harsh reality. With no vaccine in sight, several studies have been focusing on repurposing existing drugs to fight the virus. Drug repurposing refers to the reuse of existing licensed drugs to treat or prevent diseases outside the scope of their original medical purpose.
In a collaborative effort, scientists from Qatar Biomedical Research Institute (QBRI) and Qatar University (QU) have been exploring the possibility of repurposing antitumor drugs for COVID-19 treatment. What is common between viruses and many cancers and makes them both dangerous is how fast they replicate and spread in the human body.
“We started by performing a computer-based analysis of the proteins of the SARS-CoV-2 virus to explore which type of reactive metabolites would be most effective in producing proteotoxicity – damage to its proteins. Two reactive metabolites known to produce major quantitative modification of protein in physiological systems are: reactive oxygen species (ROS) and methylglyoxal (MG),” said Dr. Naila Rabbani, College of Medicine, Qatar University.
“We are in the midst of a pandemic, with time not being on our side, so repurposing an existing drug can help us find a cure much faster. Because they are already approved drugs, the conditions for safe use are known which eliminates the need for lengthy safety evaluation,” says Prof. Dr. Paul J Thornalley, Research Director of the Diabetes Research Center at the Qatar Biomedical Research Institute (QBRI), part of Hamad Bin Khalifa University, a member of Qatar Foundation.
“Upon investigating the interaction of these metabolites with the SARS-COV-2 virus, we found that the virus is likely resistant to ROS but sensitive to modification by MG on the spike protein and nucleoprotein. The spike protein is vital for virus entry into human lung cells whereas the nucleoprotein is responsible for virus replication; damaging these two would effectively result in impaired infectivity and replication. Building on some unpublished data from previously done work by myself and Prof. Rabbani at the University of Warwick, UK, we knew that certain clinically-approved anticancer drugs increase MG levels that would be high enough to modify and inactivate the SARS-CoV-2 virus in human cells,” said Prof. Thornalley.
Sensitivity to MG modification has previously been seen in other viruses including some strains of the influenza virus. Concentrations of MG 4-5 fold higher than normally found in cells is known to produce anti-viral activity.

Prof. Thornalley explained, “Having established that a pharmacological increase of MG would produce a virucidal effect and therapeutic response, we identified two antitumor drugs which increase cellular MG concentration to virucidal levels: doxorubicin and paclitaxel. We are now performing further studies on these two drugs to confirm our predictions and determine the dosage and duration of treatment that would be required for the SARS-COV-2 virus.”
Cancer drugs may be damaging to healthy cells alongside diseased cells. With that in mind, would it be safe to use them as a treatment for COVID-19?
“Since these drugs are already in clinical use, we are aware of potential adverse effects. However, most of these adverse effects are linked to dose and duration of treatment. We know that the duration of treatment against COVID-19 will be much shorter than in cancer chemotherapy. A typical course of chemotherapy is at least six months or more whereas the maximum period of treatment of COVID-19 is about one month. We don’t know about the dose required yet, but if the dose is lower or similar to that used in cancer treatment then the drugs will likely have appropriate safety for use in COVID-19 treatment,” said Dr. Rabbani.
“The elevation of MG for a short period is expected to be tolerable to human cells but much less so to the virus.”
“A recent review in the British Journal of Cancer, indicated that there are now at least 37 clinical trials on-going with anticancer drugs repurposed for COVID-19 treatment – some of which may work by our proteotoxicity approach.” said Prof. Thornalley.
“Our findings provide evidence of potential vulnerability of SARS-CoV-2 to inactivation by MG and a scientific rationale for repurposing of doxorubicin and paclitaxel for treatment of COVID-19 disease, providing efficacy and adequate therapeutic index may be established. We are currently following up on this research and evaluating the drugs – doxorubicin and paclitaxel – against SARS-CoV-2 live virus cultures at QU.” Dr Rabbani is leading this collaborative project at QU funded by a QU Emergency Response Grant. The results of our on-going research are expected by end of this year In sha Allah said Dr Rabbani.
The study is published: Al-Motawa, M.S., Abbas, H., Wijten, P., de la Fuente, A., Xue, M., Rabbani, N. and Thornalley, P.J. (2020) Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity – opportunity for repurposed chemotherapy of COVID-19 infection. Frontiers in Pharmacology. Link

 

Source: QATAR UNIVERSITY