by Disha Shantaram Shenai

Sugar to cure COVID-19?

On 8th May 2021, the Drugs Controller General of India (DCGI) granted emergency use approval to a drug called 2-deoxy-D-Glucose, also known as 2-DG. It was developed by the Institute of Nuclear Medicine and Allied Sciences (INMAS), a lab of Defence Research and Development Organisation (DRDO), in collaboration with Dr Reddy’s Laboratories, Hyderabad and is to be used as an adjuvant in treatment of COVID-19 infections.

DRDO's New Covid Drug 2-DG: All You Need To Know

So, what is 2-DG?

How does this drug function?

What are the challenges faced?

Let me try and break it down for you as per my undergraduate level of understanding.

What is 2-DG?

2-DG is an analogue of a glucose which is a simple sugar. The hydroxyl group on the second carbon atom of the glucose molecule is replaced by a hydrogen atom in 2-DG.

It is a popular anticancer agent, antiviral agent, and an anticonvulsant.

In the treatment of COVID-19 infections, 2-DG has been found to reduce the supplemental oxygen dependence by up to 42%.

Possible modes of action:

Effect on Glucose Metabolism:

Possible routes of glucose breakdown

Every  molecule of glucose we consume is broken down by a series of enzyme catalyzed reactions to produce energy for the body. This can be in the presence or absence of oxygen. However, the first step for this is common for all cells and is called Glycolysis. Glucose cannot easily diffuse into cells depending on its concentration gradient due to its high molecular weight. Thus, it enters the cell with the help of special transporters called GLUT transporters  (glucose transporters) which are present on the cell membrane. They transport glucose via facilitated diffusion. Once glucose enters the cell, glycolysis may begin in cytoplasm. It is a 10-step reaction. At the end, it produces 2 molecules of Pyruvate and energy in the form of 2 ATP molecules (via substrate level phosphorylation). Pyruvate further is converted into Acetyl CoA which enters the Krebs cycle to yield CO2 and water, producing more energy.

Slow growing tumors are usually resistant to chemotherapy. They are not vascularized and thus survive in a hypoxic environment. Despite this lack of oxygen, they undergo aerobic respiration. This is called as ‘Warburg Effect.’ Here, glycolysis occurs at a much higher rate with 10-15 times more glucose requirement to expedite energy production. Cells develop tolerance to low pH/ acidic conditions, and this further builds up hypoxia as glucose breakdown requires a lot of oxygen.

SARS-CoV-2 replication in host cells, (especially in respiratory epithelial cells) is dependent upon this type of altered glucose catabolism (like Warburg Effect).

This ensures:

What does 2-DG do?

To understand how it works, we need to know the first 2 steps of Glycolysis.

Glycolysis: Step 1 and 2

2-DG uptake is easy with the help of GLUT transporters. 2-DG is converted into 2-DG-6-phosphate by the action of the enzyme Hexokinase, which hydrolyses 1 ATP molecule to provide energy for this process. This resultant molecule does not easily cross the membranes.

2-DG-6-phosphate further inhibits the action of enzyme Hexokinase. It also prevents the action of the next enzyme in the chain i.e., Phosphohexose isomerase. This is called ‘Allosteric inhibition’. As a result, it accumulates in the cell and is not metabolised further. The cells do not get the required energy and die.

Steps 1 and 2 of glycolysis in presence of 2-DG

 

Protein Glycosylation:

Glucose analogues can interfere with the synthesis or elongation of oligosaccharides that are incorporated into proteins to form glycoproteins. They are essential components of viral envelope.

Thus, this prevents synthesis of the viral envelope and the assembly of viral particles.

The inhibition of replication of viruses by 2-DG has been found in some enveloped viruses such as influenza virus, sindbis virus and semliki forest virus, herpes simplex virus, respiratory syncytial virus, and measles virus.

Additionally, 2-DG also stops viral gene expression and viral replication by inhibition of certain transcription factors (Sp1) that regulate gene expression by altering its O-GlcNAcylation.

Things to be considered:

Targeting:

According to various clinical studies, 2-DG is relatively safe and non-toxic for humans and like any other glucose supplement, it is administered orally after the powder is mixed with water. The solution therefore reaches all cells of the body.

Then how do we achieve targeting of only the infected cells?

Most cells in the body (like adipose cells) have insulin dependent glucose uptake with the help of GLUT4 receptors except for liver, brain, kidneys, and pancreas. These are the major sites of glucose catabolism to meet the body’s energy needs. They have insulin independent glucose transporters. As a result, there is less 2-DG uptake in liver, brain, kidneys and pancreas and the normal cells of the body remain unharmed.

Additionally, it is important to note that carbohydrates are not the only source of energy. Fats and proteins are also broken down by healthy cells to meet their energy needs.

Trials, Guidelines and Costing:

We must remember that the clinical data available to us is only with respect to 330 patients. The phase II trials that began in June 2020 concerns 110 subjects while the phase III trials that began in January 2021 may continue till August and concern 220 subjects.

Many experts have also raised concerns regarding the efficacy of 2-DG in the treatment of COVID-19 infections. They have also questioned the trial evidence that led to its approval such as the blinding and the end points of the trial.

2-DG has not yet been tested on patients with severe diabetes, cardiac problems, ARDS, hepatic and renal impairment. Thus, it should be administered with caution in such patients and should not be prescribed to pregnant and lactating women, and to persons below the age of 18. 

The drug once available, will cost about 990 Rs. per sachet (each sachet contains 2.34 g). However, it should be available at discounted rates at government hospitals.

Why adjuvant therapy?

While biogenesis of viral envelope and spike proteins of SARS-CoV-2 is studied as a possible drug target, 2-DG has not been studied in this regard.

2-DG exerts multiple effects on several molecular as well as biochemical processes in the cell. So, it would be difficult to analyse an outcome with utmost certainty in vivo.

However, the metabolic benefits of using 2-DG are quite significant (reduction in oxygen dependency). Hence, it is recommended as an adjuvant therapy in treatment of SARS-CoV-2 infections.

Summary:

  • The drug is a glucose analogue with a change in the hydroxyl group at second position.
  • It works by inhibiting glucose metabolism and formation of glycoproteins.
  • Targeting is due to differential uptake in tumour and non-tumour areas of the body due to various types of GLUT receptors.
  • 2-DG stops cell proliferation of tumour cells. Good cells can use other sources such as fats and proteins to meet their energy requirement.
  • It is instrumental in reducing the oxygen dependency in COVID-19 patients. It is therefore, used as adjuvant therapy. 
  • The direct antiviral properties of 2-DG have not been studied yet along with its metabolic effects on patients with severe diabetes, cardiac, hepatic, renal problems.
  • However, as a simple molecule, it is difficult to study its metabolic effects in live cells.

References:

9th June 2021