The research team from CUHK School of Pharmacy led by Dr Billy Wai-Lung Ng (centre)Researchers from the Chinese University of Hong Kong (CUHK) have developed a novel molecule, BB56, which can potentially serve as a lead compound for the development of new drugs for neuroinflammatory disorders.
Bilobalide, a natural compound found in Gingko biloba, with favourable oral bioavailability and blood-brain barrier penetration, has long been recognized for its neuroprotective and anti-inflammatory properties, However, its complex structure and limited stability have made its development into a therapeutic agent challenging. [Phytomedicine 2026;150:1-19; J Neuroinflam 2014;11:167; Pharmacopsychiatry 2003;36:32-37; Planta Medica 2010;76:599-606; Angew Chem Int Ed 2004;43:1640-1658]
To overcome these limitations, the researchers used molecular editing, a chemical modification technique which can selectively remodel key parts of bilobalide’s complex structure while preserving its distinctive core, allowing molecules that are more stable and easier to modify to be created. Building on a 2024 study that created the precursor compound BB10, the team developed BB56, a structurally optimized derivative with strategic fluorine insertion. [Adv Sci 2026;doi:10.1002/advs.202600011]
The team first generated BB10, a chemically stabilized bilobalide analogue, via lactone-to-lactam molecular editing, and evaluated its effects in activated microglial cells. Microglia are innate immune cells of the central nervous system, and dysregulated microglial activation triggers neuroinflammation, a process implicated in conditions such as Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders.
Their earlier study showed that BB10 significantly suppressed lipopolysaccharide (LPS)-induced microglial activation and reduced levels of key inflammatory mediators, including reactive oxygen species and pro-inflammatory cytokines. Importantly, the researchers used unbiased cellular target identification (CETSA-MS) to determine how the compound exerted these effects, and identified prolyl endopeptidase (PREP) as the top thermally stabilized target, supporting cellular target engagement. BB10 inhibited PREP activity in both cellular and recombinant enzyme assays, implicating PREP inhibition as a mechanism contributing to its anti-neuroinflammatory activity.
Building on this target identification, the team developed an optimized fluorinated analogue, BB56, with improved PREP inhibition and superior anti-inflammatory efficacy, and found that PREP knockdown abrogated the anti-inflammatory effects. Mechanistically, BB56 attenuated p38/NF-κB signalling and reduced NLRP3 upregulation.
To validate the efficacy of BB56 in a living organism, the researchers assessed its anti-neuroinflammatory activity in an in vivo zebrafish model of neuroinflammation, where BB56 treatment was found to provide functional rescue with improved locomotor activity and reduced inflammatory markers. Although further studies in mammalian models and humans will be needed, the work established a new bilobalide-based chemical scaffold targeting PREP.
“Molecular editing opens new possibilities for drug development. We can create and compare a family of related molecules, identify which chemical changes improve their activity, and direct further work towards the strongest leads,” noted leader of the study, Dr Billy Wai-Lung Ng of the School of Pharmacy, CUHK. “The approach allows researchers to develop original molecules systematically from a natural starting point and explore their potential as treatments for stroke and neurodegenerative diseases such as Alzheimer’s disease.”