image: Image showing the effect of AR-12 on SARS-CoV-2 virus replication view more
Credit: VCU Massey Cancer Center
A team of scientists led by Paul Dent, Ph.D., at Virginia Commonwealth University Massey Cancer Center has discovered that an experimental cancer drug called AR-12 inhibits the SARS-CoV-2 virus, the cause of the COVID-19 pandemic, from infecting cells and replicating. Their findings were published online today in the journal Biochemical Pharmacology, and steps are now being taken to develop a clinical trial testing the novel oral treatment at VCU Health.
AR-12 has been studied extensively in Dent's laboratory as both an anti-cancer and anti-viral drug, with prior peer-reviewed publications from Dent and others showing it to be effective against viruses including Zika, mumps, measles, rubella, chikungunya, RSV, CMV, drug resistant HIV and influenza. Recently, collaboration with Jonathan O. Rayner, Ph.D., at the University of South Alabama and Laurence Booth, Ph.D., from Dent's lab, has demonstrated that AR-12 is highly effective against SARS-CoV-2.
"AR-12 works in a unique way. Unlike any other anti-viral drug, it inhibits cellular chaperones, which are proteins that are required to maintain the right 3D shape of viral proteins. The shape of the virus is critical to its ability to infect and replicate," said Dent, who is a professor in the VCU Department of Biochemistry and Molecular Biology and the Universal Corporation Chair in Cancer Cell Signaling and a member of the Cancer Cell Signaling research program at Massey.
One of the cellular chaperones inhibited by AR-12 is GRP78, which is essential for the reproduction of all viruses. GRP78 acts as a sort of cellular stress sensor and is required for the life cycle of all mammalian viruses.
Andrew Poklepovic, M.D., medical oncologist, member of the Developmental Therapeutics research program and medical director of the Clinical Trials Office at Massey, is leading efforts to translate these exciting findings into a clinical trial.
"AR-12 is an oral therapy that has been well tolerated in a prior clinical trial, so we know that it is safe and tolerable," says Poklepovic. "Most COVID-19 drugs are given intravenously, so this would be a unique therapeutic option and potentially suitable for outpatient therapy, similar to the way one would take an antibiotic."
Poklepovic hopes to begin enrolling patients in early 2021, but several milestones remain. The team must develop the clinical trial protocol, receive approval from the FDA to test AR-12 on COVID-19 patients and manufacture enough of the drug for the trial.
"For help reaching these significant milestones and moving forward with this research at the accelerated pace that we know is needed, we turned to our colleague at Massey, Said Sebti, who has extensive experience in drug development," says Poklepovic.
Sebti, Ph.D., associate director for basic research and member of the Developmental Therapeutics program at VCU Massey Cancer Center, and professor of pharmacology and toxicology at the VCU School of Medicine, attracted knowledgeable entrepreneurs to form C19 Therapeutics, which recently licensed AR-12 from VCU in order to raise funds in support of drug synthesis and clinical trial sponsorship.
"We are working to submit the required information for FDA approvals, and we are also in discussions with a local pharmaceutical company to manufacture the drug for the trial," says Sebti. "We are hopeful that AR-12 will emerge as a treatment option for patients suffering from COVID-19, ultimately saving lives and contributing to the global pandemic solution."
Another observation made in Dent's research may also shed light into why African Americans have been more affected by severe illness during the COVID-19 pandemic. People of non-European descent, particularly those with African ancestry, make a protein called ATG16L1 T300, while those with primarily European ancestry make a different variant, ATG16L1 A300.
"We compared matched colon cancer cells, with one set making A300 and the other T300, and found that cells making the T300 form made more GRP78 and more of the virus receptor ACE2," said Dent. "This, of course, does not prove that those with the T300 form are more susceptible to COVID-19, but it provides a biomarker that could be evaluated to help explain why some people get more severe illness than others."
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Recognized for its significant potential to make an impact in the fight against COVID-19, this work was supported by the VCU COVID-19 Rapid Research Funding Opportunity, which is sponsored by the Office of the Vice President for Research and Innovation and the Kenneth and Dianne Wright Center for Clinical and Translational Research. It also received funding from VCU Massey Cancer Center and the Commonwealth Health Research Board of Virginia.
Journal
Biochemical Pharmacology