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Researchers have decoded, in almost atomic detail, how an experimental molecule called EP67 activates a key receptor on human immune cells.
When added to vaccines against several viruses, including the virus that causes Covid-19, the molecule produced a stronger immune response than the vaccine alone. Representational image
What if a vaccine could trigger a stronger immune response, without triggering inflammation that can damage healthy tissue? Scientists at IIT Kanpur may have taken another step towards that goal.
Researchers have decoded, in almost atomic detail, how an experimental molecule called EP67 activates a key receptor on human immune cells. The breakthrough could help scientists design more powerful vaccine boosters and safer immune treatments.
The study has been published in the journal Proceedings of the National Academy of Sciences, or PNAS.
The 10 Amino Acid Immune Booster
EP67 is not a conventional vaccine. It is an experimental adjuvant: a substance added to vaccines to strengthen the body's immune response.
The molecule is only 10 amino acids long. Its design is inspired by C5a, a natural protein released by the body during infections. C5a helps activate the immune system and prepare it to defend itself.
But there is a problem.
Too much C5a, or prolonged exposure to it, can cause excessive inflammation and damage healthy tissue. The IIT Kanpur team essentially created a smaller, controlled version of the immune signal.
The result: EP67 activates dendritic cells and macrophages (immune cells that help develop a strong and long-lasting defense) and at the same time has a much smaller impact on neutrophils, which are closely related to excessive inflammation.
The goal: activate the immune system, without increasing the inflammatory response too much.
From Covid vaccines to MRSA
Previous studies in mice had already suggested that EP67 could have a wide range of applications.
When added to vaccines against several viruses, including the virus that causes Covid-19, the molecule produced a stronger immune response than the vaccine alone. The animals also showed signs of a faster recovery.
EP67 has also shown potential against bacterial infections, including MRSA, a strain of Staphylococcus aureus resistant to several commonly used antibiotics.
But scientists still needed to answer a fundamental question: How exactly does EP67 work?
The crucial discovery: finding the goal
The IIT Kanpur team has now identified the precise target of the molecule.
EP67 binds and activates C5aR1, a receptor located on the surface of immune cells. C5aR1 belongs to the GPCR family, one of the largest and most important groups of drug targets in the human body. About one in three prescription drugs acts through a GPCR.
To understand the mechanism, the researchers first tested EP67 in human cells grown in the laboratory. The experiments confirmed that the molecule activates C5aR1, but more mildly than natural C5a.
The team then used cryo-electron microscopy, a technology that instantly freezes molecules and captures their structures with near-atomic resolution. The images revealed the great detail.
EP67 folds into a hook shape and fits into a pocket in the center of the C5aR1 receiver. Once placed, turn on the receiver. This is the innovation: now scientists can see exactly how the molecule grabs its target.
Knowing the precise structure of the interaction could allow researchers to go beyond trial-and-error drug design. The EP67 molecule can now be redesigned. Scientists can alter its amino acid sequence to make it more stable, more precise, and potentially more effective.
The next step is to perfect its formulation and dosage through preclinical studies.
The research was led by Professor Arun K Shukla from the Department of Biological Sciences and Bioengineering at IIT Kanpur, with contributions from researchers in his laboratory and collaborators from the University of Southern California and the University of Queensland, Australia.
The study was supported by the Indian Council of Medical Research, Anusandhan National Research Foundation, Department of Biotechnology and Department of Science and Technology.
The high-resolution structure was determined at the National Cryo-EM Facility at IIT Kanpur, established with ANRF funding.
The broader significance of the discovery is clear: a molecule designed to mimic the body's own immune signals has now been located at the point where it activates immune cells.
This could provide scientists with a model for the next generation of vaccine boosters: stronger immune protection, more specific activation and potentially less harmful inflammation.
The discovery of the EP67 molecule by researchers at IIT Kanpur could lead to vaccines that trigger stronger immune responses with less inflammation.
