K.M.G.

COLLEGE OF ARTS & SCIENCE

Permanently Affiliated to Thiruvalluvar University Recognized by UGC
Under section 2(F) & 12(B) of the UGC Act 1956,
Accredited with B+ Grade by NAAC.

PG & RESEARCH DEPARTMENT OF CHEMISTRY

FIELD STUDY
ON

“AN OVERVIEW ON ANTI COVID-19 THERAPEUTIC

APPLICATION OF 2-DEOXY-D-GLUCOSE (2-DG) DRUG”

By

NAVEEN B
I.M.Sc., Chemistry
(Reg. No. 31520P14005)

With the Guidance of

Mr. B. BALAJI M.Sc., M.Phil.,

Assistant Professor,
PG & Research Department of Chemistry,
K.M.G. College of Arts & Science, Gudiyattam – 635 803.
 K.M.G. COLLEGE OF ARTS AND SCIENCE

GUDIYATTAM – 635 803.

PG & RESEARCH DEPARTMENT OF CHEMISTRY

Name : NAVEEN B

3 1 5 2 0 P 1 4 0 0 5
Register No :

FIELD STUDY

Certified that this is the bonafide report of the field study work
done by NAVEEN B , Reg. No. 31520P14005 of I . M.Sc., C h e m i s t r y , PG &
Research Department of Chemistry , K.M.G. College of Arts and Science, Gudiyattam in
the topic of “An overview on anti covid-19 therapeutic application of 2-deoxy-D-glucose
(2-DG) drug” during 2020 – 2021.

Tutor Signature HOD Signature

Faculty Signature from

other department
ABBREVIATION

iii
 ABBREVIATIONS

2-DG : 2-deoxy-D-glucose

ATP : Adenosine triphosphate

QSAR : Quantitative Structure Activity Relationship

INMAS : The Institute of Nuclear Medicine and Allied Sciences

DCGI : Drugs Controller General of India

DRL : Dr Reddy’s Laboratories

CCMB : Centre for Cellular and Molecular Biology

CDSCO : Drugs Standard Control Organization

SoC :  Standard of Care

iv
CONTENTS

v
 TABLE OF CONTENTS

S. TITLE PAGE NO
No.
1 ABSTRACT 1

2 INTRODUCTION 2

THERAPEUTIC MECHANISM OF 2-DEOXY-D-

3 11
GLUCOSE DRUG

ANTI COVID-19 THERAPEUTIC APPLICATION OF

4 16
2-DEOXY-D-GLUCOSE

5 DISCUSSIONS 23

6 CONCLUSION 26

7 REFERENCES 27

vi
 “An overview on anti covid-19 therapeutic application of

2-deoxy-D-glucose (2-DG) drug”

ABSTRACT

COVID-19, caused by severe acute respiratory syndrome coronavirus-2

(SARS-CoV-2) is a pandemic disease and is the major cause of deaths worldwide. The

clinical complexities (inflammation, cytokine storm, and multi-organ dysfunction)

associated with COVID-19 poses constraints to effective management of critically ill

COVID-19 patients. Low dose radiation therapy (LDRT) has been evaluated as a potential

therapeutic modality for COVID-19 pneumonia. However, due to heterogeneity in disease

manifestation and inter-individual variations, effective planning for LDRT is limited for

this large-scale event. 2-deoxy-D-glucose (2-DG) has emerged as a polypharmacological

agent for COVID-19 treatment due to its effects on the glycolytic pathway, anti-

inflammatory action, and interaction with viral proteins. We suggest that 2-DG will be a

potential adjuvant to enhance the efficacy of LDRT in the treatment of COVID-19

pneumonia. The ability of 2-deoxy-d-glucose (2-DG) to interfere with d-glucose

metabolism demonstrates that nutrient and energy deprivation is an efficient tool to

suppress cancer cell growth and survival. Acting as a d-glucose mimic, 2-DG inhibits

glycolysis due to formation and intracellular accumulation of 2-deoxy-d-glucose-6-

phosphate (2-DG6P), inhibiting the function of hexokinase and glucose-6-phosphate

isomerase, and inducing cell death. In addition to glycolysis inhibition, other molecular

processes are also affected by 2-DG. Attempts to improve 2-DG's drug-like properties, its

role as a potential adjuvant for other chemotherapeutics.

1
 1. INTRODUCTION

1.1 Coronavirus

The corona-like appearance of coronaviruses is caused by so-called spike

glycoproteins, Theglycoproteins, or peplomers, which are necessary for the viruses to

enter host cells. Coronaviruses are single-stranded RNA viruses, about 120 nanometers in

diameter.They are susceptible to mutation and recombination and are therefore highly

diverse.There humanThere are about 40 different varieties (see Appendix 1) and they

mainly infect humanand spreadand non-human mammals and birds.

Illustration of a coronavirus Transmission electron micrograph of Avian coronavirus

1.2 A Brief History of Coronavirus Outbreak

A novel coronavirus (CoV) named ‘2019-nCoV’ or ‘2019 novel coronavirus’ or

‘COVID-19’ by the World Health Organization (WHO) is in charge of the current outbreak

of pneumonia that began at the beginning of December 2019 near in Wuhan City, Hubei

Province, China. COVID-19 is a pathogenic virus. From the phylogenetic analysis carried

2
out with obtainable full genome sequences, bats occur to be the COVID-19 virus reservoir,

but the intermediate host(s) has not been detected till now. Though three major areas of

work already are ongoing in China to advise our awareness of the pathogenic origin of the

outbreak. These include early inquiries of cases with symptoms occurring near in Wuhan

during December 2019, ecological sampling from the Huanan Wholesale Seafood Market as

well as other area markets, and the collection of detailed reports of the point of origin and

type of wildlife species marketed on the Huanan market and the destination of those animals

after the market has been closed.

Coronaviruses mostly cause gastrointestinal and respiratory tract infections and are

inherently categorized into four major types: Gammacoronavirus, Deltacoronavirus,

Betacoronavirus and Alphacoronavirus. The first two types mainly infect birds, while the

last two mostly infect mammals. Six types of human CoVs have been formally recognized.

These comprise HCoVHKU1, HCoV-OC43, Middle East Respiratory Syndrome

coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV)

which is the type of the Betacoronavirus, HCoV229E and HCoV-NL63, which are the

member of the Alphacoronavirus. Coronaviruses did not draw global concern until the 2003

SARS pandemic, preceded by the 2012 MERS and most recently by the COVID-19

outbreaks. SARS-CoV and MERS-CoV are known to be extremely pathogenic and spread

from bats to palm civets or dromedary camels and eventually to humans.

COVID-19 is spread by dust particles and vomits while close unsafe touch between

the infector and the infected individual. Airborne distribution has not been recorded for

COVID-19 and is not known to be a significant transmission engine based on empirical

3
evidence; although it can be imagined if such aerosol-generating practices are carried out in

medical facilities. Faucal spreading has been seen in certain patients, and the active virus

has been reported in a small number of clinical studies. Furthermore, the faucal-oral route

does not seem to be a COVID-19 transmission engine; its function and relevance for

COVID-19 need to be identified.

For about 18,738,58 laboratory-confirmed cases recorded as of 2nd week of April

2020, the maximum number of cases (77.8%) was between 30 and 69 years of age. Among

the recorded cases, 21.6% are farmers or employees by profession, 51.1% are male and

77.0% are Hubei.

However, there are already many concerns regarding the latest coronavirus.

Although it seems to be transferred to humans by animals, it is important to recognize

individual animals and other sources, the path of transmission, the incubation cycle, and the

features of the susceptible community and the survival rate. Nonetheless, very little clinical

knowledge on COVID-19 disease is currently accessible and details on age span, the animal

origin of the virus, incubation time, outbreak curve, viral spectroscopy, dissemination

pathogenesis, autopsy observations, and any clinical responses to antivirals are lacking

among the serious cases.

1.3 Symptoms of corona infection

Most people infected with the COVID-19 virus will suffer from mild to moderate

respiratory infection and can be cured without special treatment. Older people and basic

medical problems such as cardiovascular disease, diabetes, respiratory disease and cancer

4
are more likely to have serious illnesses. The most common symptoms of corona are fever,

fatigue, and dry cough. Some patients may have pain, nasal congestion, runny nose, sore

throat or diarrhea. These symptoms are usually mild and start slowly. Some people get

infected but have no symptoms and don't feel well. Most people (about 5%) recover from

this illness without special treatment. 1 out of every 3 people with coronas get seriously ill

and have difficulty breathing. Your immune system responds to the infection with fever,

and usually depression. Common Signs and symptoms within 2 to 14 days are:

 Fever

 Cough

 Shortness of breath or difficulty breathing

 Tiredness

 Aches

 Runny nose

 Sore throat

1.4 Preventative Measures and Policies Enforced by WHO

Coronavirus is already an ongoing epidemic, so it is necessary to take

precautions to minimize both the risk of being sick and the transmission of the disease.

5
World Health Organization (WHO) Advice:

 Wash hands regularly with alcohol-based hand wash or soap and water.

 Preserve contact space (at least 1 m/3 feet between you and someone who

sneezes or coughs).

 Don’t touch your nose, head and ears.

 Cover your nose and mouth as you sneeze or cough, preferably with your bent

elbow or tissue.

 Try to find early medical attention if you have fatigue, cough and trouble

breathing.

 Take preventive precautions if you are in or have recently go to places where

coronavirus spreads.

1.5 2-Deoxy-D-glucose

2-Deoxy-D-glucose is a glucose molecule which has the 2-hydroxyl group replaced

by hydrogen, so that it cannot undergo further glycolysis. As such; it acts to competitively

inhibit the production of glucose-6-phosphate from glucose at

6
the phosphoglucoisomerase level (step 2 of glycolysis).  In most cells,

glucose hexokinase phosphorylates 2-deoxyglucose, trapping the product 2-deoxyglucose-

6-phosphate intracellularly (with exception of liver and kidney) thus, labelled forms of 2-

deoxyglucose serve as a good marker for tissue glucose uptake and hexokinase activity.

Many cancers have elevated glucose uptake and hexokinase levels. 2-Deoxyglucose labeled

with tritium or carbon-14 has been a popular ligand for laboratory research in animal

models, where distribution is assessed by tissue-slicing followed by autoradiography,

sometimes in tandem with either conventional or electron microscopy.

2-DG is uptaken by the glucose transporters of the cell. Therefore, cells with higher

glucose uptake, for example tumor cells, have also a higher uptake of 2-DG. Since 2-DG

hampers cell growth, its use as a tumor therapeutic has been suggested, and in fact, 2-DG is

in clinical trials. [3] A recent clinical trial showed 2-DG can be tolerated at a dose of

63 mg/kg/day, however the observed cardiac side-effects (prolongation of the Q-T interval)

at this dose and the fact that a majority of patients' (66%) cancer progressed casts doubt on

the feasibility of this reagent for further clinical use.  However, it is not completely clear

how 2-DG inhibits cell growth. The fact that glycolysis is inhibited by 2-DG, seems not to

be sufficient to explain why 2-DG treated cells stop growing. Because of its structural

similarity to mannose, 2DG has the potential to inhibit N-glycosylation in mammalian cells

and other systems, and as such induces ER stress and the Unfolded Protein Response (UPR)

pathway.

The effect of 2-deoxy-D-glucose and D-glucose on the efferent discharge rate of

sympathetic nerves was well proven with animal studies.

7
 Higher rates of glucose usage generally correlate with poor prognosis in several

types of malignant tumours. Experimental studies (both in vitro and in vivo) have shown

that 2-deoxy-D-glucose (2-DG), a glucose analog and glycolytic inhibitor, enhances

radiation-induced damage selectively in tumor cells while protecting normal cells, thereby

suggesting that 2-DG can be used as a differential radio-modifier to improve the efficacy of

radiotherapy.[10]

Clinicians have noted that 2-DG is metabolised in the pentose phosphate pathway in

red blood cells at least, although the significance of this for other cell types and for cancer

treatment in general is unclear.

Work on the ketogenic diet as a treatment for epilepsy have investigated the role

of glycolysis in the disease. 2-Deoxyglucose has been proposed by Garriga-Canut et al. as a

mimic for the ketogenic diet, and shows great promise as a new anti-epileptic drug. [11]
[12]
 The authors suggest that 2-DG works, in part, by increasing the expression of Brain-

derived neurotrophic factor (BDNF), Nerve growth factor (NGF), Arc (protein) (ARC),

and Basic fibroblast growth factor (FGF2).[13] Such uses are complicated by the fact that 2-

deoxyglucose does have some toxicity.

A study found that by combining the sugar 2-deoxy-D-glucose (2-DG)

with fenofibrate, a compound that has been safely used in humans for more than 40 years to

lower cholesterol and triglycerides, an entire tumor could effectively be targeted without the

use of toxic chemotherapy.

8
 2-DG has been used as a targeted optical imaging agent for fluorescent in

vivo imaging. In clinical medical imaging (PET scanning), fluorodeoxyglucose is used,

where one of the 2-hydrogens of 2-deoxy-D-glucose is replaced with the positron-emitting

isotope fluorine-18, which emits paired gamma rays, allowing distribution of the tracer to

be imaged by external gamma camera(s). This is increasingly done in tandem with

a CT function which is part of the same PET/CT machine, to allow better localization of

small-volume tissue glucose-uptake differences.

On May 8, 2021, the Drugs Controller General of India approved an anti-COVID

oral drug, developed by DRDO, for emergency use as adjunct therapy in moderate to severe

coronavirus patients based on this compound.The drug comes in powder form in sachet,

which is taken orally by dissolving it in water. Clinical trial results have shown that 2-DG

helps in faster recovery of hospitalised patients and reduces supplemental oxygen

dependence.

9
10
 2. Therapeutic Mechanism and application of 2-deoxy-D-glucose drug

2.1. Glucose Metabolism

Glucose is the most common source of cellular energy and a substrate for

many biochemical processes. It is typically produced from ingested dietary carbohydrates

but may also be created within the body using gluconeogenesis. The hydrophilic nature of

glucose requires specific glucose transporter proteins (GLUTs) to facilitate cellular uptake.

Higher glucose utilization by tumor cells requires overexpression of GLUT transporters to

increase glucose uptake over 20–30 fold as compared to normal cells.

Once inside the cell, glucose enters a cycle of changes to release energy in the form

of ATP. Normal cells with access to oxygen utilize glycolysis to metabolize glucose into

two molecules of pyruvate and form two molecules of ATP. The pyruvate is further

oxidized in the mitochondria to acetyl-CoA via the pyruvate dehydrogenase complex.

Acetyl-CoA then enters the Krebs cycle, in which it is oxidized into 2 molecules of CO 2.

The electrons derived from this process are used to create three molecules of NADH and

one molecule of FADH2. These electron carrier molecules are reoxidized through the

oxidoreductive systems of the respiratory chain, which drives ATP formation from ADP

and inorganic phosphate. As a result of oxidative phosphorylation, 30 ATP molecules are

generated from one molecule of glucose versus a net of 2 from glycolysis. Oxygen is vitally

important for this process as the final electron acceptor, allowing complete oxidation of

glucose. In the case of insufficient oxygen concentrations, for example in skeletal muscle

during periods of intense exertion, cells fall back on glycolysis, an ancient metabolic

pathway evolved before the accumulation of significant atmospheric oxygen. Pyruvate, the

11
end product of glycolysis, is reduced to lactate via lactic acid fermentation, cycling NADH

back to NAD+ .

2.2. Glycolysis Inhibition

For transport into the cell, 2-DG competes with glucose and can competitively

inhibit glucose transport. Oxygen deficiency, more common in the intratumoral

environment, increases the expression of glucose transporters and glycolytic enzymes,

which increases 2-DG uptake in cancer cells as compared to normal cells in an aerobic

environment. After entering the cell, 2-DG is phosphorylated by hexokinase II to 2-deoxy-

12
D-glucose-6-phosphate (2-DG-6-P) but, unlike glucose, 2-DG-6-P cannot be further

metabolized by phosphoglucose isomerase (PGI) to a 5 carbon ring. This leads to the

accumulation of 2-DG-6-P within the cell, allosteric and competitive inhibition of

hexokinase, isomerase depletion of ATP, cell cycle arrest and inhibition of cell growth,

and eventually, cell death. Therefore, the greater the amount of accumulated 2-DG-6-P,

the greater the effect on glycolysis. Inhibition of glycolysis is more effective under

hypoxic conditions, because in normoxia, cancer cells can continue to produce ATP using

alternative sources, such as fatty acids or amino acids. 

13
2.3. Preclinical and Clinical Studies of 2-DG in Anticancer Therapy

Due to its ability to inhibit glycolysis and ATP synthesis, disrupt N-glycosylation of

proteins, decrease energy metabolism and NADPH levels, and interfere with cellular thiol

metabolism, generating oxidative stress, 2-DG appears to be an efficient cytotoxic agent.

Importantly, all of these effects are mostly observed in cancer cells, without significant

effect on the viability of normal cells. Moreover, a unique ability to affect cancer cells

under hypoxic conditions, which often limits traditional cytotoxic agents, has made 2-DG a

promising candidate not only for monotherapy, but also as a component of combination

therapy with other commercially available drugs, bioactive compounds, and radiotherapy.

2.4. 2-DG and Cytotoxic Chemotherapeutics

2-DG has been tested as an adjuvant agent for various groups of clinically used

14
chemotherapeutic drugs in breast, prostate, ovarian, lung, glioma, and other cancer types. In

this testing, 2-DG has been shown to sensitize cancer cells to cytotoxic drugs to which they

are resistant when used alone.. However, in a pancreatic tumor model, 2-DG was able to

sensitize cells to 5-FU, indicating a cell-specific effect. 2-DG activity could be limited in

highly glycolytic tumors, such as pancreatic cancer, due to the high transcriptional activity of

hypoxia-inducible factor 1α (HIF-1α), leading to increased amounts of glycolytic enzymes

(mainly HK), transporting large amounts of glucose into the cell. Thus, these highly hypoxic

and/or glycolytic cancer cells require higher concentrations of 2-DG to compete with glucose

and effectively block glycolysis . In such cases, combined therapy with HIF-1α inhibitors,

such as WP1066, could restore cell sensitivity to 2-DG glycolysis inhibition. Overall, it is

plausible that 2-DG should be considered a potential adjuvant agent that has a selective, cell-

specific chemosensitizing effect, improving the efficacy of standard chemotherapeutics. It is

important to again underline the safety of 2-DG. Various animal and clinical studies

demonstrate that 2-DG is safe and relatively non-toxic in animals and humans. The most

common adverse events after a 63 mg/kg dose of 2-DG were not life threating, and included

fatigue, sweating, dizziness, and nausea, mimicking the symptoms of hypoglycemia.

2.5. 2-DG and Radiotherapy Co-Treatment

Exposure to ionizing radiation (IR) results in cell damage via production of reactive

oxygen species, as well as direct damage to nucleic acids and proteins (oxidation and bond

breakage). Despite significant improvement in therapeutic techniques, there remain tumors

with intrinsic resistance to radiation. It is well known that one of the major mechanisms of

radioresistance is hypoxic cellular environment and enhanced glycolysis. The lack of oxygen

15
leads to decreased production of reactive oxygen species, and consequently, reduced DNA

damage with radiotherapy. It has been proposed that exposure to agents that enhance

oxidative stress may sensitize cells to the cytotoxic effects of IR. Additionally, 2-DG has

been shown to inhibit DNA repair in highly glycolytic cells, such as respiratory-deficient

yeast mutants [81]. This prompted researchers to evaluate the potential of 2-DG to improve

the efficacy of radiotherapy. Several studies have demonstrated that 2-DG added prior to or

immediately after IR enhances radiation-induced cell death by modifying energy-dependent

cellular processes, such as DNA damage repair, cell cycle check points, and apoptosis. 2-DG

radiosensitization results from its effect on thiol metabolism, leading to ROS-dependent cell

death, which could be prevented by N-acetyl-l-cysteine (NAC) treatment, downregulated

glutamate cysteine ligase activity, or overexpression of ROS scavenging enzymes (e.g.,

superoxide and hydrogen peroxide).

16
 3. Anti Covid-19 therapeutic application of 2-deoxy-D-glucose

Drug Controller General of India (DCGI) approved a drug called 2-deoxy-d-glucose

(2-DG) for emergency use among people with moderate and severe COVID-19, to help

manage the disease.

This drug was jointly developed by researchers at the Institute of Nuclear Medicine

and Allied Sciences, which falls under the Defence Research & Development Organisation

(DRDO), and the pharmaceutical giant Dr Reddy’s Laboratories.

In line with the DCGI’s approval for favipiravir, itolizumab and Verafin, the approval for 2-

DG is based on poor evidence.

2-DG is a modified glucose molecule that has been found to have some therapeutic

value as an anticancer and antiviral agent. Research on 2-DG goes as far back as

1956, although it hasn’t been approved to treat any other diseases yet. It is currently mostly

used in diagnostic testing and research-related activities.

The Wire Science couldn’t find any preprint or peer-reviewed research paper uploaded by

the DRDO and Dr Reddy’s team on 2-DG clinical trials vis-à-vis COVID-19. Instead, we

had to rely on publicly available information, like a press release – from the Ministry of

Defence! – and clinical trial registrations, to access the quality of the evidence.

17
3.1 No promise of success

In news reports about the 2-DG approval, the most widely used image is from an in

entity – like the human body or humanised mice. Studies conducted inside a biological

entity are called in vivo.

(As it happens, according to one preprint paper, members of the Patanjali Research Institute

and others suggested the use of 2-DG last year. It was based, of all things, on a computer

simulation – in silico.)

This image, which the government shared in a press release, shows that cell cultures in a

laboratory without 2-DG had more viral plaques – clear spots indicating cell damage by the

virus – compared to the ones with 2-DG. These studies were conducted at the Centre for

Cellular and Molecular Biology, Hyderabad.

Image of cell cultures in an in vitro study of 2DG. Source: Ministry of Defence/Press Information Bureau

18
 While these experiments show that 2-DG can inhibit viral growth, they tell us little

about its efficacy in humans.

For example, a study published in August 2020 found that around 90 drugs that had

been approved by the US Food and Drug Administration had antiviral activity against as

SARS-CoV-2 did  ivermectin,  hydroxychloroquine,  chloroquine,  doxycycline, 

azithromycin  and  lopinavir. But none of them has been found to have any meaningful

effect in human trials with COVID-19 patients.

3.2 Setting targets after firing the gun

Based on the results from this in vitro trial, the national drug regulator had approved

a phase 2 trial for 2-DG – possibly in May 2020.

According to the press release, “Phase 2a was conducted in six hospitals and Phase

2b (dose ranging) clinical trial was conducted at 11 hospitals all over the country. Phase-2

trial was conducted on 110 patients.”

The Wire Science couldn’t find the corresponding entries for any of these trials in

the Clinical Trial Registry of India (CTRI). The reason for this discrepancy is unclear;

emails to the principal investigators of both studies hadn’t elicited a response at the time of

publishing this article. The only phase 2 trial registered for 2-DG involved 40 patients

across 12 sites.

19
 From 2009, the DCGI mandated all human clinical trials in the country to be

registered on CTRI in advance. As such, if the 2-DG trials haven’t been registered, they

would be in violation of the Indian Council of Medical Research’s ethics guidelines.

Along with making sure that a study has been approved by an ethics committee,

registering a trial on the CTRI before it begins also ensures researchers declare what

parameters they will be measuring in their study. This is a safeguard against unscrupulous

researchers measuring many different parameters and only reporting the ones that support

their hypothesis.

The DRDO and Dr Reddy’s conducted the 2-DG phase 3 trial in 220 patients at 26

sites around the country. (The DRDO is listed as the trial’s primary sponsor and Dr Reddy’s

the secondary.) However, the CTRI registration of this trial does not mention which

parameters the trial researchers plan to measure.

For example, the phase 2 registration says that the trial’s primary endpoint – the

main objective of the study – would be to measure the improvement of trial participants on

a 10-point scale. The secondary endpoint includes around 15 other measurements, like

mortality, improvement in symptoms, time spent with supplemental oxygen, etc.

So the trial will be deemed to be successful only if the researchers measure a significant

positive change on the primary endpoints – which in 2-DG’s case the researchers were

marking on the 10-point scale.

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 The CTRI registration of the phase 3 trial, however, doesn’t disclose what the

primary endpoints were.

According to the press release, in the phase 3 trial, the participants who got 2-DG

had better ‘symptom improvement’ and spent less time receiving supplemental oxygen. But

since we don’t know if these two parameters were primary endpoints of the phase 3 trial or

21
just one of the many secondary endpoints, we can’t know if the trial was a success or if the

release is only reporting the trial’s favourable findings. Also note that ‘symptom

improvement’ and oxygen dependence were secondary endpoints in the phase 2 trial.

Dr S.P. Kalantri, a professor of medicine at the Mahatma Gandhi Institute of

Medical Sciences, Sevagram, told The Wire Science that failing to declare which analyses

the researchers had decided to perform in advance destroys scientific rigour. “The data

analysed in such studies is akin to a fishing expedition — trying to find out if something

worthwhile emerges from the data. More often than not, such associations are by chance

and are spurious.”

3.3 Room for prejudice

Next, consider the results from the phase 2 trial of 2-DG. The primary endpoint of

this trial was the number of days required for the patients to score 4 or less on the

WHO’s 10-point scale to measure a COVID-19 patient’s clinical status.

There are two problems. First, this is a surrogate measurement that has little clinical

value for patients. “The study does not tell us if the drug is capable of preventing ICU

admissions, the need for mechanical ventilation or reducing deaths,” Dr Kalantri said – and

these are outcomes “that matter to the people”. Instead, the scale only tells us how a patient

might do on a subjective scale.

“For a patient with severe disease, improvement in symptoms – like cough, fever –

or reduction in oxygen use, is immaterial if the survival does not improve,” Dr Sahaj Rathi,

of the Institute of Liver and Biliary Sciences, New Delhi, said. “COVID-19 is a fatal but

22
finite disease: one either survives it or not – the outcome is clear before discharge from

hospital in nearly all cases. The outcomes which truly matter are mortality reduction in

severe disease and preventing hospitalisation in mild disease.”

Second, this 10-point scale is highly, and famously, prone to bias. There is no one-

to-one matching between a patient’s symptoms and their score on the scale. It’s up to the

doctors involved in the trial: they decide who gets a 4 and who gets a 6. And when it’s not

perfectly possible to justify each decision, there is ample room for prejudicial decision-

making.

For example, clinicians who participate in trials that are sponsored by the companies

making the drug are paid significant sums of money for their time. This compensation can

in turn encourage them to undermine the results in favour of the company.

To shield trials from such bias, they are often blinded: the clinician recording the

data doesn’t know which patients got the drug and which didn’t. Blinding is important when

researchers are measuring a subjective parameter – like a patient’s score on a 10-point scale.

Both the phase 2 and phase 3 trials of 2-DG did not blind the clinicians.

23
 4. Discussions

“The drug comes in powder form, and is taken orally by dissolving it in water. It

accumulates in the virus-infected cells and prevents virus growth by stopping their synthesis

and energy production. Its selective accumulation in virus-infected cells makes this drug

unique," it said.

India is in the midst of a vicious second wave of covid-19 infections, and a large

number of patients are needing hospitalization with supplemental oxygen support.

“The drug is expected to save precious lives given its mechanism of operation in infected

cells. This also reduces the hospital stay of covid-19 patients," it said.

“Higher proportion of patients treated with 2-DG showed RT-PCR negative conversion in

covid-19 patients. The drug will be of immense benefit to the people suffering from covid-

19," it said.

In April 2020, during the first wave of the pandemic, INMAS-DRDO scientists

conducted laboratory experiments with the help of Centre for Cellular and Molecular

Biology (CCMB), Hyderabad, and “found that this molecule works effectively against

SARS-CoV-2 virus and inhibits viral growth," the statement said.

“Based on these results, DCGI Central Drugs Standard Control Organization

(CDSCO) permitted phase-II clinical trial of 2-DG in covid-19 patients in May 2020," the

statement said.

The DRDO, along with its industry partner DRL, Hyderabad, started the clinical trials, with

phase-II trials being conducted from May to October 2020. In its phase-II trials, the drug

24
"was found to be safe in covid-19 patients, and showed significant improvement in their

recovery", DRDO said.

“Phase-II a was conducted in six hospitals and phase-IIb (dose ranging) clinical trial

was conducted at 11 hospitals all over the country. Phase-II trial was conducted on 110

patients," it said.

“In efficacy trends, the patients treated with 2-DG showed faster symptomatic cure

than Standard of Care (SoC) on various endpoints. A significantly favourable trend (2.5

days difference) was seen in terms of the median time to achieving normalization of specific

vital signs parameters when compared with SoC," the statement said.

The DCGI further permitted phase-III clinical trials in November 2020, which were

conducted on 220 patients between December 2020 and March 2021 at 27 covid-19

hospitals in Delhi, Uttar Pradesh, West Bengal, Gujarat, Rajasthan, Maharashtra, Andhra

Pradesh, Telangana, Karnataka and Tamil Nadu.

The detailed data of phase-III clinical trial was presented to DCGI.

“In 2-DG arm, significantly higher proportion of patients improved symptomatically and

became free from supplemental oxygen dependence (42% vs 31%) by day-3 in comparison

with SoC, indicating an early relief from Oxygen therapy or dependence," the statement

reads.

“A similar trend was observed in patients aged more than 65 years. On 1 May 2021,

DCGI granted permission for emergency use of this drug as adjunct therapy in moderate to

severe covid-19 patients. Being a generic molecule and analogue of glucose, it can be easily

produced and made available in plenty in the country," it said.

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 5. Conclusion

The biggest challenge in battling the novel coronavirus (nCoV-19) pandemic is the

dearth of effective therapeutic regimens. The study was aimed to assess the probable utility

of bioactive compounds, 2-deoxy-D-glucose against nCoV-19. It is noteworthy that 2-

deoxy-D-glucose have shown significant activity towards inactivating the SARS-CoV-2

viral receptors. Present results also indicate that 2-DG possess adequate oral bioavailability

without any major signs of toxicity or side effects, In sum, present in results, taken together

with the published empirical findings on the effects of 2-DG on retrovirus infected cell lines

and murine model systems, suggest that 2-DG may considerably reduce the infectivity and

virulence of nCOVID-19 by inhibiting both the entry and the replication of the virus inside

the host cells. To verify this possibility, further basic studies on model systems infected

with nCOVID-19 are necessary before human clinical trials can be conducted. In view of

the huge global devastation caused by the current viral pandemic and lack of any effective

therapy, research work to explore the therapeutic potential of 2-deoxy-D-glucose should be

urgently undertaken with well coordinated multi-institutional collaborations.

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 6. References

1.  Merck Index, 11th Edition, 2886.

2.  "Covid-19". Oxford English Dictionary (Online ed.). Oxford University Press. April 2020.

Retrieved 15 April 2020. (Subscription or participating institution membership required.)

3. ^ "Symptoms of Coronavirus". U.S. Centers for Disease Control and Prevention (CDC).

13 May 2020. Archived from the original on 17 June 2020. Retrieved 18 June 2020.

4. ^ "Q&A on coronaviruses (COVID-19)". World Health Organization (WHO). 17 April

2020.  Archived from the original on 14 May 2020. Retrieved 14 May 2020.

5. ^ Ralser, M.; Wamelink, M. M.; Struys, E. A.; Joppich, C.; Krobitsch, S.; Jakobs, C.;

Lehrach, H. (2008). "A catabolic block does not sufficiently explain how 2-deoxy-D-

glucose inhibits cell growth".  Proceedings of the National Academy of Sciences. 105 (46):

17807–17811. Bibcode:2008PNAS..10517807R. doi:10.1073/pnas.0803090105. PMC 258

4745. PMID 19004802.

6.  "DCGI approves anti-COVID drug developed by DRDO for emergency use". Press Information

Bureau, Government of India. 2021-05-08. Retrieved 2021-05-09.

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