The blood-brain barrier (BBB), a layer of specialised cells lining the brain’s blood vessels, protects the brain and maintains homeostasis, but it is also a major bottleneck in drug development. It only allows a limited range of nutrients, signalling and regulatory compounds through, and blocks >98% of therapeutics.[1,2]
Various brain delivery strategies have been proposed, yet most fail to meet expectations, and more work is needed to develop effective brain delivery. One approach relies on peptides able to cross the BBB as shuttles for drug cargoes.[1-3] In particular, animal venoms are a prime source of bioactive peptides that have evolved over millions of years to reach targets in the brain with exquisite efficiency. Thus, they boast desirable properties such as selectivity, affinity for their target, and metabolic stability. Examples of such BBB-penetrating venom peptides include apamin from bee venom and chlorotoxin from scorpion venom, both currently being studied and optimised for this application. These may well be the mere tip of the iceberg.
We are optimising an in vitro BBB platform based on a transwell human BBB cell model (hCMEC/D3)[4] to support medium-to-high throughput screening and integrating it into a venom discovery workflow. This optimised platform enables us to systematically study a wide range of peptides and fractionated venoms, supporting a new exploration of this vast biochemical landscape. Combined with integrated venomics to identify and characterise leads, we anticipate this approach will yield novel, valuable brain-penetrating peptides that can be developed into non-toxic BBB-shuttles for transporting drugs across the BBB. We expect this will have a substantial impact on future drug development strategies for brain disorders.