COVID-19 Supplements: King’s College London And Fujitsu’s Advanced Quadratic Computational Screening Identifies Vitamin B12 As A Potential Antiviral Against SARS-CoV-2.
: A new study involving researchers from King’s College London-UK, Fujitsu Technology Solutions-Spain and South London Virology Centre-UK using advanced quadratic computational screening platforms have identified Vitamin B12 as a potential antiviral against the SARS-CoV-2 coronavirus. A further detailed study involving cell cultures in the laboratory further showed that different forms of Vitamin B12 were effective as an antiviral against most of the SARS-CoV-2 emerging variants of concern or VOCs.
The discovery along with further studies could bring hope as the COVID-19 pandemic is taking a bad turn despite the advent of numerous COVID-19 vaccines due to the emergence of a variety of second and third generation variants and even recombinant and reassortant strains that are expected to become more dominant in circulation in coming weeks and months.
To date there are no effective drugs to treat COVID-19. Remdesivir is currently the only antiviral drug approved in by the US FDA for use against SARS-CoV-2, while another compound called molnupiravir is also emerging as a potential candidate.
However, both of these compounds are associated with multiple side effects, including nausea and hepatic impairment. Recent studies also showed that they could also cause dangerous cardio issues. They are also costly and therefore unaffordable in many countries and settings.
Another prospective therapeutic compound with demonstrated prophylactic, antiviral and anti-inflammatory properties is a herbal tea that combines a variety of herbs and phytochemicals in a unique patented form but is currently still struggling to get proper clinical trials and regulatory approvals due to lobbies by huge pharmaceutical firms coupled with financial constraints the company (Northern Thai Herbs) is facing.
The study team employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir (RDV) using a quantum-inspired device.
They modelled RDV and compounds present in the DrugBank database and established the optimal parameters in their algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated.
They also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12
The study team then determined the half maximal inhibitory concentration (IC50) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity.
They lastly demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta).
The study findings revealed that different forms of vitamin B12 were effective at inhibiting replication of all these variants of SARS-CoV-2. These findings suggest that vitamin B12 deserves consideration as a SARS-CoV-2 antiviral, particularly given its extended use and lack of toxicity in humans, and its availability and affordability.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.06.25.449609v1
The study team UK and Spain used a novel drug screening approach to identify compounds that could serve as effective antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19).
The researchers used a quantum-inspired device in combination with a more traditional fingerprinting method to search for drugs that are similar to remdesivir, the only antiviral against SARS-CoV-2 that is currently approved for human use.
Corresponding author Professor Dr Rocio T Martinez-Nunez from the department of Infectious Diseases, School of Immunology and Microbial Sciences, King’s College London told Thailand Medical News, “The COVID-19 pandemic has accelerated the need to identify new therapeutics at pace, including through drug repurposing.”
Although the models used predicted the antiviral drug GS-6620 as the top compound, the quantum-based model predicted the antiviral BMS-986094 as second best. Both of these compounds were initially developed to treat the hepatitis C virus.
However the more traditional Tanimoto model also predicted different forms of vitamin B12 as potential antiviral candidates.
Detailed in vitro analyses revealed that BMS-986094 and the different types of B12 were effective at inhibiting the replication of SARS-CoV-2 variants.
Dr Martinez-Nunez further added, “While BMS-986094 can cause secondary effects in humans as established by phase II trials, these findings suggest that vitamin B12 deserves consideration as a SARS-CoV-2 antiviral, particularly given its extended use and lack of toxicity in humans, and its availability and affordability. Our study data illustrate the power of employing quantum-inspired computing for drug repurposing.”
From the start of the COVID-19 outbreak in late December 2019, intense research and development efforts have led to the emergency use authorization and mass roll-out of several effective vaccines against SARS-CoV-2.
Dr Martinez-Nunez said, “However, the ongoing emergence of new variants, different immunization rates, supply chain issues, as well as the presence of smaller or larger outbreaks underlie the requirement for urgent treatments that can be rapidly deployed.”
In the pharma industry, drug repurposing refers to the process by which approved drugs are used to treat a disease they were not initially designed to treat. Virtual screening has become essential in the early stages of drug discovery, but the process is typically time-consuming since it generally relies on measuring chemical similarities between molecules.
Most well-known methods use 2D molecular fingerprints to include structural information about molecules. However, these methods do not consider aspects of molecular structures such as 3D folding.
The detailed 3D information obtained from a given molecule can be encoded as a graph, says the study team.
Dr Martinez-Nunez explained, “In order to calculate the similarity between molecules, a new graph that contains information regarding the two molecules is required, allowing for better and faster comparisons to solve an optimization problem known as the Maximum Independent Set (MIS) that extracts the similar parts of those two graphs.”
Deploying quantum-inspired computing, mathematical models are able to manage this kind of information while shortening execution times by up to 60-fold.
With remdesivir and molnupiravir exhibiting a variety of adverse effects and are extremely overpriced, Dr Martinez-Nunez added, “There is, therefore, an urgent need to identify novel antiviral compounds that exhibit low to no side effects and that are readily and economically available.”
The study team employed a Quadratic Unbounded Binary Optimization (QUBO) model that runs on a quantum-inspired device to search for compounds similar to remdesivir.
The team modeled remdesivir as a graph and then screened the DrugBank database for compounds already approved for human use. The optimal parameters in the algorithm were established, and the MIS problem was resolved within the conflict graph generated.
They also employed a more traditional fingerprint method – the Tanimoto index – that runs on a regular laptop.
Interestingly both methods predicted several compounds that exhibited similarity to remdesivir, with GS-6620 predicted as the top compound by both models. The QUBO model predicted BMS-986094 as the second-best candidate and Tanimoto predicted several forms of cobamamide, also known as vitamin B12.
The study team next performed cultured cell assays to determine the SARS-CoV-2 inhibitory capabilities of the compounds. This revealed that BMS-986094, cobamamide, hydroxocobalamin, and methylcobalamin all proved effective at concentrations lying within ranges suitable for human use.
Lastly the study team demonstrated in the laboratory that these compounds were effective at inhibiting the replication of a number of SARS-CoV-2 variants, including B.1.1.7 (also called Alpha), B.1.351 (Beta), and B.1.617.2 (Delta).
The team concluded that the study data revealed novel compounds that could inhibit SARS-CoV-2 replication, based on the QUBO model and the more traditional Tanimoto fingerprint.
They said, “BMS warrants further investigation, while vitamin B12 is readily available from multiple sources. It is affordable, can be self-administered by patients, is available worldwide, and displays low-to-no toxicity at high doses. Our screening method can be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.”
The team along with researchers from other institutions is continuing additional research on the effectiveness of Vitamin B12 to treat COVID-19.
Vitamin B12 also known as cobalamin, is a water-soluble vitamin involved in metabolism. It is one of eight B vitamins. It is a cofactor in DNA synthesis, in both fatty acid and amino acid metabolism. It is important in the normal functioning of the nervous system via its role in the synthesis of myelin and in the maturation of red blood cells in the bone marrow.
The most common cause of vitamin B12 deficiency in developed countries is impaired absorption due to a loss of gastric intrinsic factor (IF) which must be bound to a food-source of B12 in order for absorption to occur. A second major cause is age-related decline in stomach acid production (achlorhydria), because acid exposure frees protein-bound vitamin. For the same reason, people on long-term antacid therapy, using proton-pump inhibitors, H2 blockers or other antacids are at increased risk. Deficiency may be characterized by limb neuropathy or a blood disorder called pernicious anemia, a type of megaloblastic anemia. Folate levels in the individual may affect the course of pathological changes and symptomatology of vitamin B12 deficiency.
Vitamin B12 is a coordination complex of cobalt, which occupies the center of a corrin ligand and is further bound to a benzimidazole ligand and adenosyl group. It is a deep red solid that dissolves in water to give red solutions.
A number of related species are known and these behave similarly, in particular all function as vitamins. This collection of compounds, of which vitamin B12 is one member, are often referred to as "cobalamins". These chemical compounds have a similar molecular structure, each of which shows vitamin activity in a vitamin-deficient biological system, they are referred to as vitamers. The vitamin activity is as a coenzyme, meaning that its presence is required for some enzyme-catalyzed reactions.
-cyanocobalamin, the adenosyl ligand in vitamin B12 is replaced by cyanide.
-hydroxocobalamin, the adenosyl ligand in vitamin B12 is replaced by hydroxide.
-methylcobalamin , the adenosyl ligand in vitamin B12 is replaced by methyl.
Cyanocobalamin is a manufactured form of B12. Bacterial fermentation creates AdoB12 and MeB12, which are converted to cyanocobalamin by addition of potassium cyanide in the presence of sodium nitrite and heat. Once consumed, cyanocobalamin is converted to the biologically active AdoB12 and MeB12.
Cyanocobalamin is the most common form used in dietary supplements and food fortification because cyanide stabilizes the molecule against degradation. Methylcobalamin is also offered as a dietary supplement.
Hydroxocobalamin can be injected intramuscularly to treat vitamin B12 deficiency. It can also be injected intravenously for the purpose of treating cyanide poisoning, as the hydroxyl group is displaced by cyanide, creating a non-toxic cyanocobalamin that is excreted in urine.
"Pseudovitamin B12" refers to compounds that are corrinoids with a structure similar to the vitamin but without vitamin activity. Pseudovitamin B12 is the majority corrinoid in spirulina, an algal health food sometimes erroneously claimed as having this vitamin activity.
Vitamin B12 deficiency is most commonly caused by low intake, but can also result from malabsorption, certain intestinal disorders, low presence of binding proteins, or use of certain medications. Vegan ie individuals who choose to not consume any animal-sourced foods are at risk because plant-sourced foods do not contain the vitamin in sufficient amounts to prevent vitamin deficiency. Vegetarians or people who consume animal byproducts such as dairy products and eggs, but not the flesh of any animal are also at risk.
Interestingly Vitamin B12 deficiency has been observed in between 40% and 80% of the vegetarian population who do not also take a vitamin B12 supplement or consume vitamin-fortified food. In Hong Kong and India, vitamin B12 deficiency has been found in roughly 80% of the vegan population. As with vegetarians, vegans can avoid this by consuming a dietary supplement or eating B12 fortified food such as cereal, plant-based milks, and nutritional yeast as a regular part of their diet. The elderly are at increased risk because they tend to produce less stomach acid as they age, a condition known as achlorhydria, thereby increasing their probability of B12 deficiency due to reduced absorption.
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