2-Deoxy-D-glucose

2-Deoxy--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 the phosphoglucoisomerase level (step 2 of glycolysis). 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 up taken 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. 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.
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.
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. 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). 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.
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.
Resistance to 2-DG has been reported in HeLa cells and in yeast; in the latter, it involves the detoxification of a metabolite derived from 2-DG (2DG-6-phosphate) by a phosphatase. Despite the existence of such a phosphatase in human (named HDHD1A) However it is unclear whether it contributes to the resistance of human cells to 2DG or affects FDG-based imaging.
COVID-19 treatment.
On May 8, 2021, the Drugs Controller General of India approved an oral drug, based on 2-deoxy-D-glucose, for emergency use as adjunct therapy in moderate to severe coronavirus patients. It was developed by the Institute of Nuclear Medicine and Allied Sciences Laboratory of DRDO along with Dr. Reddy's Laboratories, who claimed via a press release, that the drug "helps in faster recovery of hospitalised patients and reduces supplemental oxygen dependence". The Wire as well as The Hindu noted that the approval was based on poor evidence; no journal publication (or preprint) concerning efficacy and safety are yet available.
Based on a successful "in vitro" study at Centre for Cellular and Molecular Biology in April 2020, wherein 2-DG exhibited anti-COVID properties, permission was granted for Phase II trials which were supposedly conducted over 110 patients across multiple sites in two phases from May 2020 to October 2020 but yet did not feature over Clinical Trials Registry of India (CTRI). The logged Phase II trial featured a cohort of 40 patients only; the primary end point was taken as days needed to improve on WHO's Clinical Progression Scale and received criticism for not being an objective parameter. The Phase-3 trial happened in 220 patients across 26 sites from December 2020 to March 2021; the CTRI entry did not record any primary endpoint. Both the two trials did not blind the clinicians. At doses lower than the prescribed regimen, older trials had recorded grade 3 QT prolongation and hyperglycemia.
Dr. Reddy's Laboratories will be manufacturing the drug for treating patients in India's second wave of COVID.