1. Anti-COVID-19 drug developed by DRDO gets emergency use nod

An analogue of glucose, it can be easily produced

The Drugs Controller General of India (DCGI) has granted permission for emergency use of an anti-COVID-19 therapeutic application of the drug 2-deoxy-D-glucose (2-DG), developed by 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, Hyderabad.

In a release issued on Saturday, the Ministry of Defence said that as per the order, emergency use of this drug as adjunct therapy in moderate to severe COVID-19 patients is permitted. It added that being a generic molecule and analogue of glucose, it can be easily produced and made available in plenty in the country.

The drug comes in powder form in sachets and is taken orally by dissolving it in water. It accumulates in the virus infected cells and prevents their growth by stopping viral synthesis and energy production. Its selective accumulation in virally infected cells makes this drug unique.

Clinical trial results have shown that this molecule helps in faster recovery of hospitalised patients and reduces supplemental oxygen dependence, noted the release. It further said that higher proportion of patients treated with 2-DG showed RT-PCR negative conversion in COVID-19 patients.

In April 2020, during the first wave of the pandemic, INMAS-DRDO scientists conducted laboratory experiments with the help of the Centre for Cellular and Molecular Biology (CCMB), Hyderabad, and found that this molecule works effectively against SARS-CoV-2 virus and inhibits the viral growth.

The DCGI permitted Phase-II clinical trial of 2-DG in COVID-19 patients in May 2020.

In Phase-II trials (including dose ranging) conducted during May to October 2020, the drug was found to be safe in COVID-19 patients, and showed it led to significant improvement in their recovery.

Phase IIa 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.

In efficacy trends, patients treated with 2-DG showed faster symptomatic cure than Standard of Care (SoC) on various endpoints.

About 2-DG drug

• The drug ensures faster recovery of hospitalised patients and will reduce supplemental oxygen dependence during clinical trials.
• It accumulates in infected cells and stops viral synthesis. This accumulation makes the drug unique.
• The drug comes in a powdered form in sachets. It is consumed orally after dissolving in water.
• It was developed by Institute of Nuclear Medicine and Allied Sciences (INMAS). INMAS is a laboratory operating under DRDO.
• The DGCI has granted permission for emergency use of the drug in moderate to severe COVID-19 patients.
• 2-DG is a generic molecule and thus can be easily produced and made available in plenty in the country.

How are 2-DG accumulated in the cells?

The 2-DG is a glucose molecule. It cannot undergo further glycolysis. Glycolysis is the process in which free energy is released. The 2-DG molecules are up taken by the glucose transporters of the cell. The glucose transporters are membrane proteins that facilitate the transport of glucose across plasma membrane. This is how the drug reaches the cells. As it cannot undergo glycolysis it simply stays in the cells. Continuous intake of the drug thus leads to accumulation in the cell.

2-DG as Tumour therapeutic

The cancer cells have higher glucose uptake. Thus, when 2-DG is injected into cancer patients, it acts as a good marker for cancer cells.

2. E.U., India relaunch FTA talks, sign connectivity partnership

Delhi, however, fails to secure support for proposal on vaccine IP waiver

India and the European Union agreed on Saturday to relaunch free trade negotiations by resuming talks that were suspended in 2013 for the Bilateral Trade and Investment Agreement (BTIA), as Prime Minister Narendra Modi interacted virtually from Delhi with President of the European Commission Ursula Von der Leyen and E.U. Council President Charles Michel along with 27 European leaders gathered in Porto, Portugal, on Saturday.

The E.U.-India leaders meeting also discussed COVID recovery plans and vaccine cooperation, adopted a Connectivity Partnership document outlining plans to cooperate on digital and infrastructure projects, and signed the contract for the second tranche of $150 million from the E.U. for the Pune Metro rail project.

However, India failed to secure the support of the European leaders for its proposal at the World Trade Organisation at the meeting for patent waivers for COVID vaccine, and government officials said they hoped to see the E.U. continue to debate the issue. President of the European Commission

Briefing the media at the end of the meeting, Ms. Von Der Leyen and Mr. Michel said a greater imperative at present was for countries to ramp up the production and delivery of SARS-Cov-2 vaccines through greater investment.

“There are different feelings about the [Indian] request from around the world… In the short term many of us think that this may not be the magic solution, but we would like to keep a closer eye and keep discussing the issue,” said Mr. Michel. Ms. Von Der Leyen said the E.U., which was the “pharmacy of the world” and had exported 50% of its production of 400 million vaccine doses to other countries, had shown the way forward. India, which is facing vaccine shortages during the current crisis has had to halt its export programme for vaccines worldwide.

When asked about the E.U. hesitation over supporting the proposal jointly presented by India and South Africa at the WTO, MEA officials pointed that the U.S. had recently changed its stand and now supports the idea of waiving intellectual property rights on vaccines for the duration of the pandemic, and India would therefore watch the “evolving E.U. position on this”. The support of a major bloc like the E.U. is crucial to passing the resolution at the WTO by consensus.

The joint statement issued after the meeting said India and the E.U. agreed to work towards a “balanced, ambitious, comprehensive and mutually beneficial trade agreement which would respond to the current challenges,” and launch negotiations for a “stand-alone” investment protection agreement and a separate agreement on “geographical indications” pertaining to intellectual property rights.

Hailing the decision by the leaders to resume trade negotiations for the BTIA as a “remarkable moment”, Ms. Von Der Leyen said the talks that had begun in 2007, and stalled in 2013, will finally be picked up again.

The talks had run into trouble over market access issues, and tariffs by India on products like wine, dairy and automotive parts, as well as E.U. resistance over visas for Indian professionals. In addition, the Modi government’s decision to scrap all Bilateral Investment Treaties (BITs) in 2015 posed hurdles for new E.U. investments in India. The timing and structure of the relaunched talks would be steered by the recently set up High-Level dialogue between Commerce Minister Piyush Goyal and his counterpart, EU Trade Commissioner, said MEA Secretary (West) Vikas Swarup.

The India-E.U. connectivity partnership signed on Saturday also committed the two sides to working together on digital, energy, transport, people to people connectivity that was “transparent, viable, inclusive, sustainable, comprehensive, with a rules-based approach”.

The partnership is seen as a response to China’s Belt and Road Initiative, and comes as the E.U.’s negotiations with China on their Comprehensive Agreement on Investment (CAI) have run into trouble.

3. Wildlife forensics helps cause of pangolins

Researchers sequenced 624 pangolin scales, categorising the species

Pangolins, despite being listed in Schedule I of Wildlife (Protection) Act, 1972 continue to be the world’s most trafficked mammal. The primary demand for its scales in the making of traditional East Asian medicines has led to an estimated illegal trade worth $2.5 billion every year. To enforce the appropriate national and international laws and to track the decline of the species, researchers of Zoological Survey of India (ZSI), Kolkata, have now developed tools to tell apart the scales of Indian pangolin (Manis crassicaudata) and Chinese pangolin (Manis pentadactyla).

They characterised the morphological features and investigated genetic variations between the two species by sequencing 624 scales of pangolins and comparing the sequences with all eight pangolin species. Based on the size, shape, weight and ridge counts on the scales, the team was able to categorise the two species.

“These simple morphological characters can be easily measured by the use of a simple Vernier caliper. These metric characters will be of immense utility for the law enforcement agencies for taking spot decision during larger seizures,” says Mukesh Thakur, lead author and the Coordinator of Wildlife Forensic Facilities at ZSI. The results were recently published in Forensic Science International.

Estimating casualty

He explains that when scales are confiscated, the wildlife officers just weigh and estimate how many pangolins might have been killed. “This needs revision as the dry weight of the scales from one single mature Chinese pangolin is roughly about 500 to 700 grams. However, in the case of Indian pangolin it goes up to 1.5 kg to 1.8 kg,” explains Dr. Thakur.

“Studies have shown that between 2000 and 2019, an estimate of about 8,95,000 pangolins was trafficked globally, which mainly involved Asian and African pangolins. This has led to a drastic decline of the species. According to the International Union for Conservation of Nature, Indian pangolins are endangered and the Chinese pangolins are critically endangered. Therefore, it is important to develop protocols that can readily identify species and the number of individuals poached in seizures,” explains first author Prajnashree Priyambada, a PhD scholar at the University of Calcutta.

“Though the Chinese pangolin is distributed mostly in Vietnam, Thailand, Cambodia, the northeastern part of our country is also its home. The population is already limited as it has a limited geographical range, low fecundity with just one offspring a year. It is also facing pressure due to habitat degradation and is prone to local extinction,” adds Dr. Thakur.

Skill-building workshops

“We have been conducting training and skill-building workshops for the law enforcement agencies like various officials of forest department, police, revenue department and wildlife crime control bureau and this method of identifying scales will also be demonstrated soon. Forest guards, customs officials or the airport authority when they undertake search and seizure don’t have much of a clue about identification. This study has laid out the methods to take a spot decision, which is crucial to prosecuting the case in the court of law,” adds Dr. Thakur.

Pangolins in India

• Out of the eight species of pangolin, the Indian Pangolin (Manis crassicaudata) and the Chinese Pangolin (Manis pentadactyla) are found in India.
• Indian Pangolin is a large anteater covered by 11-13 rows of scales on the back. A terminal scale is also present on the lower side of the tail of the Indian Pangolin, which is absent in the Chinese Pangolin.
• Habitat
  • Indian Pangolin is widely distributed in India, except the arid region, high Himalayas and the North-East. The species is also found in Bangladesh, Pakistan, Nepal and Sri Lanka.
  • Chinese Pangolin is found in the Himalayan foothills in Eastern Nepal, Bhutan, Northern India, North-East Bangladesh and through Southern China.
• Threats to Pangolins in India: Hunting and poaching for local consumptive use (e.g. as a protein source and traditional medicine) and international trade for its meat and scales in East and South East Asian countries, particularly China and Vietnam.
• Protection Status
  • IUCN Red List
    • Indian Pangolin: Endangered
    • Chinese Pangolin: Critically Endangered
  • Both these species are listed under Schedule I, Part I of the Wildlife (Protection) Act, 1972.

4. Study reveals interesting facet of the novel coronavirus

The nucleocapsid or N protein and not just the spike protein may play a role in the infectivity of SARS-CoV-2

Studies of the coronavirus have largely focused on its ‘spike’ protein. A new study from IISER Bhopal has found that other proteins, in particular, the nucleocapsid or ‘N’ protein may also be responsible for the infectivity of the virus.

SARS-CoV-2 structure

The SARS-CoV-2, or novel coronavirus, consists of an RNA genome contained in a spherical capsule which has many proteins, one of which is the ‘spike’ protein that gives it its characteristic spiky surface or ‘crown’. These spike proteins are the ones that help the virus penetrate and enter the body of human hosts. This is therefore used as a target by those developing vaccines as well as drugs. In order to test the effect of these formulations on the virus, scientists often use not live virus particles but ‘pseudotype’ them. That is, they use a core which is a different, harmless virus, encapsulate it in a lipid–protein sphere which has spikes on them made by the spike protein. Usually only the spike protein is used in pseudotyping. However, in real situations, the spike protein does not act in isolation but in conjunction with other proteins.

Hence the IISER Bhopal team was curious to study the effect of combinations of proteins on the infectivity of the virus. In their study they used vectors of lentivirus that they had pseudotyped with not only the spike protein but with 24 other proteins in all, including the N protein. “We use lentivirus-derived vectors that have been proven really safe to handle inside the labs to study virus-entry processes,” says Ajit Chande from the Department of Biological Sciences at IISER, Bhopal, who led the study, in an email.

Combination effect

The infectivity of each of pseudoviruses containing the 24 proteins was tested separately, and the group found that the pseudovirus containing the nucleocapsid ‘N’ protein had higher infectivity than the others.

The researchers used an assay where the extent of infectivity can be readily quantified using either enzymatic activity or fluorescence. “For this, we included a pair of reporter genes in the pseudoviruses (lentiviral vectors), which when delivered to the target cells expresses both an enzyme (called “luciferase”) and a green fluorescent protein,” explains Sreepadmanabh, an author of the paper published in Frontiers in Cellular and Infection Microbiology.

“After allowing the viral infection to occur, we measured the level of enzyme activity and counted the number of cells showing fluorescence, which gave a quantitative estimation of how infectious the virus would have been,” adds Tarun Mishra, also an author of the paper. The inference was that stronger the signal, higher was the infectivity.

These results were found to hold when they studied the so-called U.K. variant also. “The results which hold true for the original spike protein remain unchanged in the case of this mutant as well – the N protein, when included, leads to the production of more infectious viral particles,” says Dr Chande.

More possibilities

According to him, this discovery opens up exciting possibilities. “Ongoing or planned studies which seek to screen neutralising antibodies or therapeutic drugs could benefit by incorporating the N protein as a part of their experimental setup while using such pseudotyping systems,” says Dr Chande.

“This would help obtain more physiologically relevant infectivity levels and help set a proper threshold for such preliminary screenings which could improve their success rate.”

As Dr Chande says, this work also highlights a new role for the N protein, which is worth further investigation by itself. “It is possible that a more comprehensive understanding of the impact of the N protein on the spike may help identify key portions of these proteins which help mediate this effect. Such segments could then be specifically targeted using drugs to disrupt this process,” he adds.