Since the outbreak from Wuhan, COVID-19 has infected over 5 million people and caused the death of 350 thousand worldwide. There are no regulatory approved drugs specific for COVID-19 patients, despite the fact that much effort has been put into finding or developing effective drugs for the treatment of the disease, or vaccines to prevent the disease. Therefore, repurposing of existing drugs, which already have the regulatory approval or are in the late stages of clinical trials, is the main direction of clinical research for COVID-19 treatment nowadays. This blog post will explain the reason for this phenomenon and how these drugs are chosen.
To develop a new drug to be used for a disease, its functions against the disease need to be tested on cellular level, and then on animal modals. After that it has to undergo 3 phases of clinical trials to test the safety, effectiveness, efficacy, and side effects on humans, which usually takes years. Even after passing all the clinical trials, manufacturing and distributing the new drug at the scale needed to tackle this pandemic, can also be significantly challenging. On the other hand, the drugs currently being used to treat other illnesses have been carefully examined before and found to be safe to use. Moreover, as these drugs have existed for quite a while, they are cheap to produce, easy to manufacture, and are scalable. Furthermore, the dosage information is largely in hand. Therefore, they can be used immediately if they are proven to be effective for COVID-19 treatment.1,2
You may have heard of Remdesivir (a drug developed for Ebola), or Chloroquine / Hydroxychloroquine (malaria medications), quite frequently from the news recently. However, apart from those, there are dozens more existing drug candidates currently being tested for COVID-19, some as a single entity or some in combination, in over 1000 clinical trials worldwide as of 18th May from the data of Cytel's global COVID-19 clinical trial tracker.3,4
You may have heard of Remdesivir (a drug developed for Ebola), or Chloroquine / Hydroxychloroquine (malaria medications), quite frequently from the news recently. However, apart from those, there are dozens more existing drug candidates currently being tested for COVID-19, some as a single entity or some in combination, in over 1000 clinical trials worldwide as of 18th May from the data of Cytel's global COVID-19 clinical trial tracker.3,4
As there are huge numbers of existing drugs or compounds, you may wonder how these are being selected to be tested for COVID-19 treatment. Ideally, the findings about 1) the genetic components and the structure of the virus; 2) the molecular mechanisms involving in the virus invasion to the host; and 3) the biological reactions, including the immune response, in COVID-19 cases, are useful to help looking for candidate drugs. For example, two anti-inflammatory drugs were selected by scientists in the UK for COVID-19 treatment as cytokine storm, resulting from the hyper-reaction of the host immune system, is observed in serious cases.5 However, the molecular mechanisms underlying the virus invasion is not much understood as the disease has newly emerged. This limits the finding of drugs to be tested.
A study conducted by a group of scientists from multiple disciplines, mainly from the San Francisco area, gives us a good example of how the selection of drugs and compounds is made for a newly emerged disease, when not many molecular mechanisms are known.6 The study first started by sequence analysis of available SARS-CoV-2 isolates, and identified 29 viral proteins to be translated and processed from the 14 open reading frames in the virus genome. Based on the analysis results, the scientists then cloned 26 of the 29 viral sequences into streptavidin-tagged expression vectors. Using the 26 tagged viral protein as baits, they were able to identify 332 high-confidence SARS-CoV-2-human protein-protein interactions in human embryonic kidney cells by affinity purification mass spectrometry.
By analysing these virus-human protein-protein interactions, the molecular mechanisms underlying the virus infection becomes clearer. These interactions unveiled the molecular pathways in protein trafficking, translation, transcription, and ubiquitination in the infected cells. Moreover, the interactome also unveiled the molecules involved in several innate immune signalling pathways. Any drugs/compounds able to intervene with the interactions could be candidates to be tested for treatment of COVID-19.
The finding of these interactions enable the scientists to identify 62 human proteins that are targeted by existing drugs or compounds: 29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds. These drugs and compounds were then examined with their antiviral activity. Preliminary results showed that protein biogenesis inhibitors (zotatifin, ternatin-4, and PS3061), and ligands of the Sigma1 and Sigma1 receptors (haloperidol, PB28, PD-144418 and hydroxychloroquine), are effective in reducing viral infectivity.*
Besides identifying drugs by first identifying molecular mechanisms underlying the viral infection from laboratory experiments, artificial intelligence (AI) has been started to be used in searching for drugs repurposed for a newly emerged pandemic.7,8,9,10,11 By feeding in 1) databases of existing drugs or compounds, or 2) data on the molecular structures of the drugs and the virus, and 3) data on research findings of the molecular mechanisms of diseases or symptoms that may be involved, and by making use of the training/algorithm system for analysis, AI is able to help scientists to find candidate drugs without performing any laboratory work. However, as with the other method, selected drugs are still needed to be tested for their antiviral efficiency on a cellular level before proceeding to clinical trials.
According to Cytel's global COVID-19 clinical trial tracker, there are currently a dozen popular drugs being tested for their efficiency in the treatment of COVID-19. In my next blog post, I am going to introduce these drugs and their functions, and explain the reason of their being chosen for clinical studies.
*The main drawback of this study is the lack of an in vivo experiment to proof the in vitro findings of the interactome. The 26 viral proteins were ectopically expressed in modified embryonic kidney cells. Further verification of the expression of the viral proteins and those virus-human protein-protein interactions in the commonly infected cells should be performed in the future. Apart from this, the study was undertaken very nicely, providing quite a full picture of the molecular mechanisms underlying the virus invasion in just 2 to 3 months since the viral outbreaks.
References
1. "Repurposing existing drugs for COVID-19 a more rapid alternative to a vaccine, say researchers" Research news of the University of Cambridge. https://www.cam.ac.uk/research/news/repurposing-existing-drugs-for-covid-19-a-more-rapid-alternative-to-a-vaccine-say-researchers
2. S.P.H. Alexander, J. Armstrong, and A.P. Davenport, et al. A rational roadmap for SARS-CoV-2/COVID-19 pharmacotherapeutic research and development. IUPHAR review 29. British Journal of Pharmacology; 1 May 2020; DOI: 10.1111/bph.15094.
3. K. Thorlund, L. Dron, and J. Park, et al. A real-time dashboard of clinical trials for COVID-19. The Lancet, published online April 24, 2020. https://doi.org/10.1016/S2589-7500(20)30086-8.
4. Global coronavirus COVID-19 trial tracker. https://www.covid19-trials.com/
5. "National trial launched to find Covid-19 treatment" Addenbrook's Hospital news, 16th May, 2020. https://www.cuh.nhs.uk/news/communications/national-trial-launched-covid-19-treatment.
6. David E. Gordon, Gwendolyn M. Jang, Mehdi Bouhaddou, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. 2020 Apr 30. doi: 10.1038/s41586-020-2286-9.
7. N.L. Bragazzi, H. Dai, G. Damiani, et al. How Big Data and Artificial Intelligence Can Help Better Manage the COVID-19 Pandemic. Int J Environ Res Public Health. 2020 May 2;17(9):E3176. doi: 10.3390/ijerph17093176.
8. McCall, B. COVID-19 and artificial intelligence: Protecting health-care workers and curbing the spread. Lancet Digit. Health 2020, 2, e166-e167.
9. P. Richardson, I. Griffin, C. Tucker, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet 2020, 395, e30-e31.
10. Y. Ke, T. Peng, T.Yeh, et al. Artificial intelligence approach fighting COVID-19 with repurposing drugs. 2020 May 15. doi: 10.1016/j.bj.2020.05.001.
11. "AI VIVO identifies list of 31 drugs that show potential for Covid-19 treatment" Cambridge Independent, 22nd April, 2020. https://www.cambridgeindependent.co.uk/business/ai-vivo-identifies-list-of-31-drugs-that-show-potential-for-covid-19-treatment-9107179/
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