DRDO along with DRL developed a new drug called 2DG to control the second wave of the COVID-19 pandemic.
Scientists are finding different ways to contain the spread of the SARS-CoV-2 virus by developing vaccines and repurposing antiviral therapies as possible treatments. In April 2020, the Institute of Nuclear Medicine and Allied Sciences (INMAS), a lab of the Defence Research and Development Organisation (DRDO) in collaboration with Dr Reddy’s Laboratories (DRL) developed 2-deoxy-D-Glucose or 2DG. The researchers studied the antiviral effects of 2DG and conducted clinical trials which showed that 2DG aided in faster recovery and reduced oxygen dependence in COVID-19 patients. Earlier this month, the Drug Controller General of India (DCGI) approved the emergency use of 2DG as an additive therapy for moderate to severe SARS-CoV-2 infections. On May 17th, 2021, the first batch of 2DG was released by the Union Health Minister Dr Harsh Vardhan and Defence Minister Rajnath Singh.
Studies on 2DG as an antiviral agent:
2DG or 2-deoxy-D-glucose is a glucose analogue where the hydroxyl (-OH) moiety at the 2nd position is replaced by a hydrogen molecule. This drug is primarily used in its radiolabelled form for the diagnosis of several cardiovascular disorders, Alzheimer’s and cancer. The unique nature of 2DG is that it can selectively attack virus-infected cells. The therapeutic nature of 2DG as an anticancer and antiviral drug is still under investigation.
In a 2018 paper published in the journal PNAS, Gualdoni et al studied how 2DG controlled the replication of Rhinovirus. They first tested the drug in rhinovirus infected HeLa cells. 2DG was found to inhibit the processes of glycolysis (breakdown of glucose) and glycosylation (adding a glucose moiety onto a protein). 2DG binds to the phosphoglucoisomerase instead of glucose, rendering the enzyme inactive and thereby halting the process of glycolysis. If glycolysis is restricted, ATP production and carbon influx are impaired which can cease all the necessary metabolic pathways that are crucial for the virus to survive.
2DG induces the unfolding process of several proteins by interfering with N-linked glycosylation and hence hindering rhinovirus replication. In mice models, the researchers observed that 2DG reduced rhinovirus induced inflammation. They also observed that there were no toxic side effects in the mice affirming that 2DG was safe and non-toxic. From these experiments, the scientists concluded that 2DG induces metabolic starvation causing the virus to die.
Balkrishna et al did a study (publication not yet peer-reviewed) to understand the preventative effects of 2DG on SARS-CoV-2 replication through simulated computer models. Through these studies, they observed that the drug binds efficiently to the spike receptors of the virus. 2DG also halted viral replication by inactivating the viral protease and viral endonuclease. Due to the inhibition of glycolysis caused by the 2DG drug, through a series of cascading events, p53 protein gets activated. P53 protein is an antiviral agent that can arrest the SARS-CoV-2 cell cycle.
Scientists at INMAS and CCMB (Centre for Cellular and Molecular Biology) added 2DG to the culture media for SARS-CoV-2. The number of viral plaques in these media plates were found to be much lesser than that of the control media plates indicating the antiviral nature of 2DG. DRDO and DRL conducted clinical trials to test its therapeutic efficiency in humans. Phase II clinical trials took place between May- November 2020 in 11 hospitals across the country involving 110 patients. The primary outcome was to observe the change in viral load and to assess the improvement of symptoms based on a WHO scoring pattern. Patients who took 2DG along with standard care improved 2.5 days earlier than those who did not take the drug.
Phase III trials were done from November 2020 onwards to test the safety and efficacy of 2DG. Among 220 COVID-19 patients, a higher proportion that was treated with 2DG showed the RT-PCR negative conversion without any toxicity or side effects. The patients also exhibited fewer intense symptoms and lesser oxygen dependence (42% to 31%) by day 3 of taking 2DG.
2DG is a powdery drug that can be dissolved in water and consumed orally, without causing any harmful side effects. The drug can be easily prepared from glucose molecules and made available all across the country. “In the ongoing second COVID-19 wave, a large number of patients are facing severe oxygen dependency and need hospitalisation. The drug is expected to save precious lives due to the mechanism of operation of the drug in infected cells. This also reduces the hospital stay of COVID-19 patients,” stated the Ministry of Defence in the press release.