The Novo Nordisk Foundation has awarded a research grant to Priscilla Yang, Professor of Microbiology and Immunology at Stanford School of Medicine, to begin developing novel antiviral medicines for combatting a deadly virus that has the potential to unleash the next pandemic.
Four years ago, very few people had heard of SARS-CoV-2. Today, everyone knows about COVID-19.
Similarly, few people today know about henipaviruses such as Nipah virus and Hendra virus, but just as COVID-19 held the world in an iron grip for two years, these viruses have the potential to do this in the future. In addition, the problem is that there are no vaccines or treatments for henipaviruses, so if a large outbreak occurs tomorrow, we will again be quite defenceless.
However, a USD 2.5 million grant from the Novo Nordisk Foundation will seek to redress this situation. The grant has been awarded to Priscilla Yang, Professor and research leader at Stanford School of Medicine, for developing prototypes of drugs that not only can be used to combat henipaviruses, but also to validate new methods to combat other viruses that threaten humanity in the future.
To carry out this task, Priscilla Yang has allied herself with some of the world’s most talented researchers in the field: Nathanael Gray from Stanford University in Stanford, California, Jianwei Che from the Dana-Farber Cancer Institute in Boston, Sean P.J. Whelan from Washington University in St. Louis, Missouri, Hector Aguilar-Carreno from Cornell University in Ithaca, New York and Anne Moscona from Columbia University in New York City.
“Nipah virus and Hendra virus infections in human can have high fatality rates. Due to zoonotic spillover from animals to humans and transmission between humans in close contact, they are considered to be both dangerous and to have high pandemic potential. The COVID-19 pandemic taught us that vaccines are not the only solution, because they do not always prevent transmission and because some people are either unable to tolerate vaccines or do not mount good immune responses. Further, transporting vaccines to remote parts of low-income countries is often difficult. Small molecule antiviral drugs can therefore provide an important complement to combatting these viruses,” explains Priscilla Yang.
Henipaviruses have been transmitted from animals to humans in several cases in Malaysia and Bangladesh, where they cause high mortality and serious nervous system complications among the people who survive.
The grant has been awarded for the project ‘Pilot Studies to Develop Small-molecule Inhibitors and Degraders Targeting Henipavirus’ through the Pandemic Antiviral Discovery (PAD) initiative established by the Novo Nordisk Foundation, Open Philanthropy and the Bill & Melinda Gates Foundation. The PAD initiative has awarded a total of 14 grants for research projects aiming to develop solutions to combat henipaviruses.
Targeting two viral proteins
The researchers led by Priscilla Yang aim to develop small molecules that can prevent viruses from multiplying in human cells.
The researchers’ ambition is to target two henipavirus proteins. One is the viral polymerase, which is essential for making the virus’s genome. The researchers will develop small molecules that inhibit the polymerase’s function so that replication of the viral genome is arrested.
As a second approach, the researchers will develop small molecules that target a surface protein on viruses. This surface protein, called the F protein, has the same function as the spike protein in SARS-CoV-2 and enables the virus to infect cells.
Finally, the researchers will develop small molecules that target the polymerase and F proteins for degradation by the host, an approach known as targeted protein degradation. This pharmacological strategy is being broadly pursued in cancer biology but has had limited application in infectious disease. Proof of concept studies suggest that both cancer cells and viruses may have a more difficult time evolving resistance to drugs with this mechanism.
“The work we have proposed is ambitious – identifying and developing drug leads and validation of targeted protein degradation as an antiviral approach are major tasks. Each laboratory would not be able to tackle these goals alone, but together we believe we can achieve the project goal,” says Priscilla Yang.
Capable of combatting viruses in general
Priscilla Yang hopes that the researchers will be able to develop small molecules to combat the polymerase and F protein during the 3-year project period and that they can validate their effectiveness in experiments on cells.
In the slightly longer term, another aim is to investigate whether the antiviral medicines developed are effective in animals.
In addition, the researchers also hope that the project will enable them to develop methods to design antiviral medicines that can combat not only henipaviruses but also other viruses.
“The goal of developing molecules that bind to viral proteins and induce their degradation is a new concept. We are testing this concept on henipaviruses but hope that we can establish a general principle for developing antiviral medicines that can be used in future virus pandemics,” concludes Priscilla Yang.
About the Pandemic Antiviral Discovery (PAD) initiative
The Novo Nordisk Foundation, Open Philanthropy and the Bill & Melinda Gates Foundation entered into an agreement in 2022 on the Pandemic Antiviral Discovery (PAD) initiative, which aims to support research on developing new antiviral medicines to combat future pandemics.
Initially, the three organisations agreed to allocate USD 90 million for projects aimed at developing antiviral medicines for Phase 2 trials to combat viruses such as henipaviruses, coronaviruses, paramyxoviruses and orthomyxoviruses.
The PAD initiative’s first Request for Proposals focused on research targeting henipaviruses, which have an estimated mortality rate between 40% and 75%. You can read more here.