Scientists at Sanford Burnham Prebys Medical Discovery Institute, the University of Hong Kong, Scripps Research, UC San Diego School of Medicine, the Icahn School of Medicine at Mount Sinai and UCLA have identified 30 existing drugs that stop the replication of SARS-CoV-2, the virus that causes COVID-19.
Almost all of the drugs are entirely different from those currently being tested in clinical trials, and weren’t previously known to hold promise for COVID-19 treatment.
The new candidates expand the number of “shots on goal” for a potential COVID-19 treatment and could reach patients faster than drugs that are created from scratch.
The study was placed on bioRxiv, an open-access distribution service for preprints of life science research.
“We believe this is one of the first comprehensive drug screens using the live SARS-CoV-2 virus, and our hope is that one or more of these drugs will save lives while we wait for a vaccine for COVID-19,” says Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and senior author of the study.
“Many drugs identified in this study – most of which are new to the COVID-19 research community – can begin clinical trials immediately or in a few months after additional testing.”
Screening a library of known drugs
The drugs were identified by screening more than 12,000 drugs from the ReFRAME drug repurposing collection- a library of existing drugs that have been approved by the FDA for other diseases or have been tested extensively for human safety.
ReFRAME was created by Scripps Research with support from the Bill & Melinda Gates Foundation to accelerate efforts to fight deadly diseases.
Every compound was tested against the live SARS-CoV-2 virus, isolated from patients in Washington State and China, and the final 30 drugs were selected based on their ability to stop the virus’s growth.
“For us, the starting point for finding any new antiviral drug is to measure its ability to block viral replication in the lab,” says Chanda.
“Since the drugs we identified in this study have already been tested in humans and proven safe, we can leapfrog over the more than half decade of studies normally required to get approval for human use.”
Early access to live SARS-CoV-2 virus
Chanda’s team partnered with the scientist who discovered the first SARS virus, Kwok-Yung Yuen, M.D., chair of Infectious Diseases at the University of Hong Kong; and Shuofeng Yuan, Ph.D., assistant research professor in the Department of Microbiology at the University of Hong Kong, who had access to the live SARS-CoV-2 virus in February 2020.
Together, the labs re-created Chanda’s automated high-throughput drug screen in Yuen’s lab, where it was used to identify 300 drugs from the ReFRAME library that could keep cells alive despite infection with SARS-CoV-2.
These 300 drugs advanced to a second round of testing in Chanda’s lab in La Jolla, Calif., where the researchers used molecular tools such as polymerase chain reaction (PCR) and immunofluorescence microscopy to pinpoint 30 compounds that were the most effective at stopping viral replication
New drugs emerge as promising candidates for COVID-19 treatment
Highlights of the scientists’ discoveries follow. Each drug or experimental compound requires further evaluation in clinical trials to prove its effectiveness in treating people with COVID-19 before it can be used broadly.
- 27 drugs that are not currently under evaluation for COVID-19 were effective at halting viral replication. 17 of these drugs have an extensive record of human safety from clinical studies in non-COVID-19 diseases, including four – clofazimine, acitretin, tretinoin and astemizole – that were previously approved by the FDA for other indications.
- Thus far, six of the 17 were shown to be effective at concentrations, or doses, likely to be effective and tolerable in humans. Four of these six drugs – apilimod, MLN-3897, VBY-825 and ONO 5334 – have been tested clinically for diseases including rheumatoid arthritis, Crohn’s disease, osteoporosis and cancer.
- In addition to the 27 drug candidates, three drugs currently in clinical trials for COVID-19, including remdesivir and chloroquine derivatives, were also shown to be effective at stopping the growth of SARS-CoV-2. These results reaffirm their promise as potential COVID-19 treatments and support the continuation of ongoing clinical trials to prove their effectiveness in patients.
- Depending on regulatory guidance, the newly identified drug candidates may proceed directly to COVID-19 clinical trials or undergo further testing for efficacy in animal models.
“Based on the extensive data in this study, we believe the four drugs described above – apilimod, MLN-3897, VBY-825 and ONO 5334 – represent the best new approaches for a near-term COVID-19 treatment,” says Chanda.
“However, we believe that all 30 drug candidates should be fully explored, as they were clearly active and effective at halting viral replication in our tests.”
Chanda’s team was able to work with the live virus because his laboratory is certified as biosafety level 3, or BSL-3, which means it’s equipped with safeguards to protect lab personnel – as well as the surrounding environment and community – from pathogens that can cause serious or potentially lethal disease.
The facility was established in 2016 to support Chanda’s research on broad-spectrum antivirals – drugs that work against many viruses – for HIV, influenza, Dengue fever and West Nile virus.
Support for the research
“We were only able to generate these rapid results thanks to many years of support from the National Institutes of Health (NIH) and the Department of Defense (DoD), both funded by taxpayers, and the generosity of philanthropists,” says Chanda, “This support enabled us to build the infrastructure and teams that were fully trained and ready to go when it was time to do this important work.
We have chosen to release these findings to the scientific and medical community now to help address the current global health emergency,” Chanda continues.
“The data from this drug screen is a treasure trove; and we will continue to mine the data from this analysis, with a goal to find additional candidate therapies – and combinations of drugs – as they are identified.”
The Chanda team is grateful to the lab of Adolfo Garcia-Sastre, Ph.D., professor in the Department of Microbiology and co-director of the Global Health & Emerging Pathogens Institute at the Icahn School of Medicine at Mount Sinai, who provided critical help and reagents for the viral assays in the study.
The first authors of the study are Laura Riva, Ph.D., a postdoctoral research fellow in the Chanda lab at Sanford Burnham Prebys, and Shuofeng Yuan at the University of Hong Kong, who contributed equally to the study. Additional study authors include Xin Yin, Laura Martin-Sancho, Naoko Matsunaga, Lars Pache, Paul De Jesus, Kristina Herbert, Peter Teriete, Yuan Pu, Courtney Nguyen and Andrey Rubanov of Sanford Burnham Prebys; Jasper Fuk-Woo Chan, Jianli Cao, Vincent Poon and Kwok-Yung Yuen of the University of Hong Kong; Sebastian Burgstaller, Peter G. Schultz, Andrew Su, Mitchell V. Hull, Tu-Trinh Nguyen and Arnab K. Chatterjee of Scripps Research; Max Chang and Christopher Benner of UC San Diego School of Medicine; Luis Martinez-Sobrido, Thomas M. Moran, Wen-Chun Liu, Lisa Miorin, Kris M. White, Jeffrey R. Johnson, Randy Albrecht and Adolfo Garcia-Sastre of the Icahn School of Medicine at Mount Sinai; and Ren Sun of UCLA.
Candidate: LAM-002 (apilimod)
Type: Selective first-in-class, oral PIKfyve kinase inhibitor being developed in B-cell non-Hodgkin lymphoma and amyotrophic lateral sclerosis/frontotemporal dementia
Status: AI Therapeutics co-founder Jonathan Rothberg, PhD, told GEN the company is preparing INDs for submission to the FDA, with the goal of launching clinical trials of LAM-002 in COVID-19 in the second quarter.
He citing new data that he said showed the drug was effective in cell assays in inhibiting the entry of SARS-CoV-2 through its first-in-class molecular mechanism. SAM-002 can also be combined with other antiviral drugs, which typically target other molecular mechanisms, like viral replication.
AI is looking to combine SAM-002 with Gilead Sciences’ Remdesivir, said Rothberg, recipient of the 2013 National Medal of Technology and Innovation in Engineering for pioneering inventions and commercialization of next generation DNA sequencing technologies.
AI is collaborating with Yale University Medical School (clinical studies), and Zhejiang University (nonclinical).
AI Therapeutics and collaborators have shown that in cell cultures, LAM-002 was effective alone and lowered the level of SARS-CoV-2 virus even more when combined with Gilead Sciences’ Remdesivir. “We have 50,000 pills ready to go, we have a drug that has been shown to be safe in 800 patients, and we just made a commitment for 110,000 more pills and material for 5 Million more,” Rothberg added.
Apilimod(STA 5326) mesylate is a potent IL-12/IL-23 inhibitor, IL-12 production in cultures of IFN-r/LPS-stimulated human PBMCs is strongly inhibited by STA-5326 with an IC50 of 10 nM. IC50 value: 10 nM (IFN- /LPS-stimulated human PBMCs)  Target: IL-12/IL-23 in vitro: STA-5326 not only inhibited IL-12, but it also potently inhibited IL-23 and total p40 products in various forms as monomer, homodimer, and heterodimerin IFN- /SAC-stimulated human PBMCs .
STA-5326 inhibited IFN-r production induced by either IFN- /SAC or SAC in human PBMCs, with an IC50 of approximately 20 nM, while the compound had no significant effect on the production when T cells were stimulated using anti-CD3 and anti-CD28 antibodies, suggesting that the T-cell-receptor-dependent production of IFN- that occurs independently of suppression of Th1 cells via inhibition of IL-12 is not directly inhibited by the compound . in vivo: Patients with CD responded within 14 days of treatment with apilimod and, after 28 days, the drug significantly reduced the Crohn’s disease activity index (CDAI).
Apilimod is currently in phase II clinical trials for rheumatoid arthritis, common variable immunodeficiency and CD. From the data available to date, apilimod appears to be a promising treatment for CD, and the oral formulation of this compound provides an advantage for apilimod over injectable therapies .
Oral administration of either 5 mg/kg or 20 mg/kg STA-5326 reduced the severity of EAU on day 14 and 18. In addition, mice treated with 20 mg/kg STA-5326 showed significantly decreased severity of EAU by histopathological analysis .
The ReFRAME collection of 12,000 compounds is a best-in-class drug repurposing library containing nearly all small molecules that have reached clinical development or undergone significant preclinical profiling.
The purpose of such a screening collection is to enable rapid testing of compounds with demonstrated safety profiles in new indications, such as neglected or rare diseases, where there is less commercial motivation for expensive research and development.
To date, 12,000 compounds (80% of compounds identified from data mining) have been purchased or synthesized and subsequently plated for screening. In addition, an open-access data portal (https://reframedb.org) has been developed to share ReFRAME screen hits to encourage additional follow-up and maximize the impact of the ReFRAME screening collection.
The website can be searched by structure or text string.
For Example searching for Malaria highlights a number of known therapeutic agents.