The Drugs Controller General of India (DCGI) recently approved a drug, 2-deoxy-D-glucose (2-DG) for emergency use, as a adjunct therapy in treating moderate to severe cases of Covid-19. This drug is developed by the Defence Research and Development Organisation (DRDO) in collaboration with Dr. Reddy’s laboratories in Hyderabad, helped faster recovery of hospitalized patients and decreased dependence on supplemental oxygen in clinical trials.
What is 2-DG?
2-DG is similar to glucose molecule ( analog of glucose ) in which a hydroxy (OH) group is replaced by hyderogen (H). This analog of glucose will compete with normal glucose molecule in different biochemical pathways within our cells.
Virus infection of cells , 2-DG and Glycolysis :
In case of infection by SARS CoV2 in covid19 patients, the virus controls the host cell by modifying different aspects of its metabolism. This is crucial for virus to replicate quickly and spread to infect neighboring cells. One such pathway is glycolysis , where dietary glucose is converted to 2 molecules of pyruvate and 2 ATP’s (energy currency of cell) . The pyruvate formed is oxidised to acetyl co enzyme – A , which enters krebs cycles to yield more energy in form of 30 ATP’s and 2 molecules of CO2.
Similar to cancer cells , virus infected cells also loves high levels of glucose in the cell. Elevated levels of glucose enhances viral replication and further spread of infection. Infection of lung cells by the virus leads to rapid upregulation of angiotensin-converting enzyme 2 (ACE2), a key SARS-CoV-2’s receptor for entering the cells. This finally culminates into so called cytokine storm, where our own immune system works in a aberrant manner to produce high levels of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. This leads to death of our own healthy cells which eventually cause organ failure and death.
2-DG and Glycolysis block
The amount of glucose available to cell eventually decides the fate of cell in covid infected patients. The more the available glucose , the better are the conditions for virus to spread. Since glucose is a starting material for energy producing pathways like glycolysis and krebs cycles, blocking these pathways in infected cells might be a way to stop virus from spreading.
The glucose analog 2-DG , which lacks a OH group is blocked at the first step in glycolysis and gets accumulated in infected cells. This will make cell deficient in ATP source and glycolysis intermediates, which are essential for cell survival and proliferation, thereby causing cell growth arrest and death.
2-DG looks similar to glucose and can bind to glucose transporters on cell membrane. Once it enters the cells it can compete with normal glucose during glycolysis process, eventually blocks the pathway completely. Since infected cells requirement of glucose will be more than normal cells, infected cells ends up taking more 2-DG than normal cells.
However one needs to careful as there might be some side effects as normal cells also might uptake 2-DG, but the damage will be much lesser than the benefit that we get . One more thing to note that it is not a antiviral drug as it just accumulates in infected cells and blocks a vital component required for synthesis of new viral particles ( in this case glucose is blocked in glycolysis pathway).
Reference:
- Enzymatic features of the glucose metabolism in tumor cells.Herling A, König M, Bulik S, Holzhütter HGFEBS J. 2011 Jul; 278(14):2436-59.
- Ardestani, A., Azizi, Z. Targeting glucose metabolism for treatment of COVID-19. Sig Transduct Target Ther 6, 112 (2021). https://doi.org/10.1038/s41392-021-00532-4
- Related article : https://www.scoopwhoop.com/news/what-is-drdo-2-dg-oral-covid-19-drug-said-to-reduce-oxygen-dependency/