From venoms to peptide brain delivery systems

Brain diseases are among the least understood and poorly treated conditions, yet their incidence rate continues to increase due to our growing and aging population. Delivery of therapeutics to the brain is a major challenge with >98% of drug candidates developed for brain diseases not being commercialised due to their inability to reach their target. This is due to the existence of the bloodbrain barrier, a biological barrier that tightly controls the transfer of substances between the blood and the brain, protecting us from toxic compounds while gating important nutrients and signalling molecules through. Venomous animals have evolved highly efficient venom compositions that have secured the survival of their species for hundreds of millions of years. A typical venom comprises hundreds of neurologically active molecules, many of which have been optimised to reach targets in the opponents central nervous system for predation or defence purposes. Some of these are also able to cross the human blood-brain barrier to reach the central nervous system. In this project, we will systematically screen for such venom compounds to learn more on how these molecules are able to cross the blood-brain barrier. We will use this knowledge to develop new strategies for the targeted transport of novel substances into the brain, thereby improving the brain uptake of therapeutics for the treatment and expanding opportunities for future studies of brain diseases. Further outcomes include a set of molecules that will provide blueprints for new and highly innovative therapeutic brain delivery systems. In the long term, this research direction has the potential to transform the landscape on how we study and treat brain disorders.

This project explored nature's most venomous animals to discover molecules that could help transport new medicines into the brain to boost our medical programs in the fight against brain diseases and neurological disorders. The blood-brain barrier (BBB) safeguards our brain from harm but poses a colossal challenge in delivering therapeutics. Existing methods struggle to breach this barrier, limiting drug effectiveness. Imagine if we could harness molecules, refined over millions of years by nature's venomous creatures, to escort vital medicines into our brains in a safe manner. In this project, we developed a new discovery platform that enables us to screen venoms from various animals for hidden gems, namely molecules that evolved to sneak through the BBB. Our discovery platform allows us to identify such BBB-penetrating molecules, which not only will help us to understand the BBB gating mechanisms but, with the help of cutting-edge medicinal chemistry, also allows us to develop non-toxic and safe BBB shuttles to get much-needed medicines efficiently into the brain for better treatment options. Our work could usher in a new era of safer and more effective therapies for a broad range of conditions like Autism, Multiple Sclerosis, Depression, Dementia, Post-traumatic stress disorders, Alzheimer's, Parkinson's, and other neurological disorders. This project represents the first important stepping stone in an exciting new area of biomedical research.