New research into malaria suggests targeting enzymes from the human host, rather than from the pathogen itself, could offer effective treatment for COVID-19, besides offering faster treatment for a range of many diseases.
The international study, led by RMIT University’s Professor Christian Doerig, proposes a strategy that could save years of drug discovery research and millions of dollars in drug development with the help of repurposing existing treatments meant for other diseases such as cancer.
The approach shows promise for its potential application in the fight against COVID-19 pandemic that has gripped the entire world with over 700,000 deaths already. Published in Nature Communications, the study showed that the parasites that cause malaria are heavily dependent on enzymes in red blood cells where the parasites hide and proliferate.
Antibody array data showing activation of kinases in human red blood cells infected with the malaria parasite / CREDIT: RMIT University
Since there are drugs developed for cancer which inactivate these human enzymes, known as protein kinases, to effectively kill the parasite.This method represents an alternative to drugs that target the parasite itself, instead of focusing on enzymes. During the infection, the host cell enzymes were activated revealing novel points of target when the parasite exists in human body host.
Lead author, RMIT’s Dr Jack Adderley, said,”These host enzymes are in many instances the same as those activated in cancer cells, so we can now jump on the back of existing cancer drug discovery and look to repurpose a drug that is already available or close to completion.”
Repurposing of Drugs in Future
In addition to enabling the repurposing of drugs, the approach is likely to reduce the drug resistance, as the pathogen cannot escape by simply mutating the target of the drug, as is the case for many available antimalarials, he noted. Moreover, this approach has the potential to considerably reduce the cost and accelerate the deployment of new and urgently needed antimalarials, explained Dr Adderley.
Doerig, Associate Dean for the Biomedical Sciences Cluster at RMIT and senior author of the paper, described the findings as exciting since as drug resistance is one of the biggest challenges in modern healthcare.
“By targeting the host and not the pathogen itself, we remove the possibility for the pathogen to rapidly become resistant by mutating the target of the drug, as the target is made by the human host, not the pathogen,” said Doering.
Doerig’s team will now collaborate with the Peter Doherty Institute for Infection and Immunity (Doherty Institute) to investigate potential COVID-19 treatments using this approach. Doherty. a Nobel laureate, is known already as vocal voice about the Covid-19 treatment and vaccines.
Finally, a Covid-19 vaccine developed by Oxford University’s Jenner Institute and licensed to the multinational pharmaceutical company, AstraZeneca has emerged as the favourite of World Health Organization scientists out of about 23 vaccines in their Phase III trial, after reporting success and safety in the first two phases.
For India, this vaccine is important as AstraZeneca, among others, had entered a deal with Pune-based Serum Institute of India to supply one billion doses for low-and-middle-Income countries, with first 400 million to be produced before the end of 2020. Its other global facilities will produce 300 million doses for the US.
Between April 23-May 21, Oxford University with AstraZeneca conducted human trials of the vaccine – where 1,077 volunteers were given the AZD1222 shot and all of them developed protective neutralizing antibodies as well as T-cells (T lymphocytes) which multiplied to attack any pathogen inside the human system. The participants were aged between 18 and 55 and split roughly 50-50 between male and female. Ninety-one percent of them were white, while roughly 5% were Asian, and fewer than 1% were Black.
While AZD1222 enters the next phase III of the clinical trials, the results published in The Lancet medical journal, show that the Covid-19 vaccine prompted no serious side effects among the people who received two doses so far, which has promted the WHO Chief Scientist Michael Ryan, the World Health Organization’s health emergencies chief to say: “We now need to move into larger scale, real-world trials, but it is good to see more data, more products moving in to this very important phase of vaccine discovery.” See the video below from 19:30 for WHO remarks on Oxford vaccine:
The next stage — Phase III — trial will be conducted in the US on 30,000 patients, besides those “in low-to-middle income countries including Brazil and South Africa which are already underway,” the university has said in a release.
Sarah Gilbert, professor of vaccinology at Oxford University, had earlier informed that 8,000 volunteers were enrolled for the Phase III trial which will assess how the vaccine works in a large number of people over the age of 18, and how well the vaccine works to prevent them from the infection. However, it will take a year to conclusively determine if the vaccine offers long-term protection or not.
“There is still much work to be done before we can confirm if our vaccine will help manage the COVID-19 pandemic… We still do not know how strong an immune response we need to provoke to effectively protect against Sars-Cov-2 infection,” said Gilbert.
Indian Serum Institute Role
Pascal Soriot, chief executive of AstraZeneca, said the company was on track to be producing doses by September. While the Oxford University will have intellectual property rights, Pune-based Serum Institute of India will emerge as a major supplier.
The data, published in the medical journal the Lancet, showed that the vaccine caused side effects such as fever, headaches, muscle aches, and injection site reactions, in about 60% of patients, which are deemed mild and not dangerous for any vaccine.
The Oxford-AstraZeneca vaccine AZD1222 has finally emerged as a relatively safe vaccine in view of similar results or data from others is still awaited from 22 other contestants who are in Phase III trial. In case its immediate rival vaccine from the Chinese biotech CanSino, the Phase 2 results showed that this vaccine works better in some people and not equally efficient among those aged 55 and older, a key target for Covid-19 vaccination.
Advantages of Oxford vaccine over Moderna vaccine
While the AZD1222 vaccine went on trials from April 30 with a 10,000-patient study in the United Kingdom, another 5,000-patient test began in Brazil in June and the current phase 3 results could become available in September, October, or November, said Astra-Zeneca.
AZD1222 has another advantage as it needs to be kept cold, but not frozen, whereas the messenger RNA vaccines work on the body’s genetic messaging system to provoke an immune response. The mRNA vaccines, developed by Moderna, the German firm BioNTech and the drug giant Pfizer, increased levels of neutralizing antibodies in patients.
WHO Scientist Michael Ryan announcing the Oxford vaccine trial results at a press conference Monday, July 20, 2020 (WHO)
AZD1222 works differently using a genetically engineered virus, called adenovirus, which was taken from chimps and modified not to replicate and sicken people. It carries a gene for one of the proteins in SARS-Cov-2 and inserts it into a recipient’s cells, which in turn, cause the patient’s cells to make that protein, which is then recognized by the immune system as foreign. This mechanism was not there in the past but has been used in experimental vaccines such as the Ebola virus and the virus that causes Middle East respiratory syndrome (MERS).
Oxford vaccine vs CanSino
The next rival CanSino, also into its Phase 3 trial, is a viral vector vaccine that uses a live but weakened human cold virus, adenovirus 5 — known as Ad5 for short — to develop immune system of the body to recognize the SARS-CoV-2 coronavirus. Its focus is on the Ad5 parts of the vaccine rather than the SARS-Cov-2 and many research groups have stopped it over concerns about preexisting immunity, which can run to 70% or higher in some populations.
CanSino Phase 2 trial essentially showed that those who had no or low-level pre-existing immunity to Ad5 developed neutralizing antibodies to SARS-CoV-2 at roughly double the rate of people who had high-level preexisting immunity, especially in people aged 55 and older. CanSino has dropped the higher dose.
Kathryn Edwards, scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tenn., noted the CanSino vaccine may not be protective enough for older adults, but it might be useful in children. However, the CanSino vaccine has already received an emergency license in China for use in the military.
Japan’s National Institute of Advanced Industrial Science and Technology (AIST) and IIT-Delhi joint research on Indian ayurvedic component Ashwagandha in combinaton with propolis, an actve ingredent from New Zealand can be developed as possible drug treatment to cure Coronavirus or COVID-19.
The research by IIT-D was led by Professor D Sundar from DAILAB (DBT-AIST International Laboratory for Advanced Biomedicine) discovered that Withanone (Wi-N), a natural compound derived from Ashwagandha (Withania somnifera) and Caffeic Acid Phenethyl Ester (CAPE), an active ingredient of New Zealand propolis, have the potential to block the activity of Mpro, responsible for COVID-19 infection in the human body. Japan’s AIST has not made any such claim so far and either removed the relevant sections and pages from its website or put them Under Construction mode.
The study to be published in Journal of Biomolecular Structure and Dynamics soon, claimed that properties of the ayurvedic herb Ashwagandha have “therapeutic and preventive value” against COVID-19 infection. “SARS-CoV-2 virus genome and structure have been recently published triggering drug designing, devising and development using informatics and experimental tools, worldwide.
DAILAB and AIST Japan, working on natural compounds from Ashwagandha and propolis for last several years, explored the possibility of some of their bio-actives to interact with SARS-CoV-2,” IIT-D said in a statement. The journal JBSD ranks 57 out of 286 in the category of journals in biochemistry and molecular biology, 12 out of 73 in the category of journals in biophysics.
“The researchers targeted the main SARS-CoV-2’s enzyme for splitting proteins, known as the Main protease or Mpro that plays a key role in mediating viral replication. This is an attractive drug target for this virus… They discovered that Withanone (Wi-N), a natural compound derived from Ashwagandha (Withania somnifera) and Caffeic Acid Phenethyl Ester (CAPE), an active ingredient of New Zealand propolis, have the potential to interact with and block the activity of Mpro,” the statement said.
Sundar said, “While the reputation of Ashwagandha as an immunity enhancer forms a basis of the recent initiative of the Indian government in forming an interdisciplinary task force to launch its clinical research studies related to SARS-CoV-2 and the Covid-19 disease, the current research report of this team provide hints on its direct anti-viral activities.”
However, Japan’s AIST has not made any such claim so far and either removed the relevant sections and pages from its website or put them Under Construction mode.
