Megabodies: a new tool for innovative applications in research and drug discovery

3 January 2019
The Jan Steyaert lab at the VIB-VUB Center for Structural Biology developed an innovative plug and play technology to rigidly graft functional Nanobodies® on several scaffolds with diverse properties to build Megabodies. Such Megabodies are game changing research tools in cryo-electron microscopy, a transforming technique for the high-resolution structure determination of biomolecules in solution. The team of Radu Aricescu at the MRC Laboratory of Molecular Biology in Cambridge, UK, applied the Megabody technology successfully, which lead to major new insights in the structure and functional mechanisms of human GABAA receptors. These results are published today in two back to back publications in Nature.

From Nanobodies to Megabodies
More than 20 years ago the first natural single-domain antibodies, called Nanobodies, were serendipitously discovered in the serum of a dromedary camel in the laboratory of Professor Raymond Hamers at the Vrije Universiteit Brussel (VUB). The easy discovery of antigen-specific VHHs and their beneficial biochemical properties (size, affinity, specificity, stability) and easy engineering have boosted their use as research tools in biotechnology and medicine and laid the basis for a cluster of Biotech companies in Flanders including AgroSavfe, Camel-IDs, Confo Therapeutics and Ablynx, a Sanofi Company.

The small size of the Nanobodies is an advantage in a lot of cases, but for several applications there was a need for large and rigid equivalents of these Nanobodies. That is why the team of Professor Steyaert developed the innovative Megabody technology, where functional Nanobodies are rigidly grafted on several scaffolds with diverse properties.

Essential tool for cryo-electron microscopy
As reported in two back to back publications in Nature, such Megabodies turned out to be an essential research tools in cryo-electron microscopy which allows high-resolution structure determination of biomolecules in solution. Using Megabodies developed at the Steyaert lab, the team of Radu Aricescu at the MRC-LMB managed to solve the structure of a major synaptic human GABAA receptor in complex with a range of small molecules including the classical benzodiazepines alprazolam (Xanax) and diazepam (Valium). GABAA receptors are the main mediators of rapid inhibitory neurotransmission in the vertebrate nervous system, and among the most important human drug targets owing to their many allosteric sites, which bind compounds with anticonvulsant, anti-anxiety, analgesic, sedative and anaesthetic properties.

Prof. Radu Aricescu (MRC-LMB): “Benzodiazepines such as Valium and Xanax entered clinical use decades before the identity of their receptors was known. Despite their widespread use, they have undesirable side effects including addiction and sedation. Our structural work has uncovered their binding modes and way of working, important steps towards developing improved therapeutic strategies.”

Prof. Jan Steyaert (VIB-VUB): “This work underlines the potential of Megabodies to overcome a fundamental challenge in single particle cryoEM that small proteins do not produce enough contrast in noisy projection images to precisely determine their orientation. By binding our large and rigid Megabodies to small (drug) targets, we produce larger and more homogeneous particles that vitrify with less preferential orientations.”

Solving protein structures by single particle cryogenic electron microscopy has become a crucial tool to study the interactions of drugs with challenging yet highly valuable human drug targets. Specifically, these structures might lead to the rational design of safer and more specific drugs.

Megabody technology license agreement
Confo Therapeutics, an emerging drug discovery company, today also announces that it has entered into an agreement with VIB for an exclusive, worldwide license to VIB’s ‘Megabody’ technology for applications on GPCRs.

Commenting on the deal, Dr. Cedric Ververken, Confo Therapeutics’ CEO, said: “The Megabody technology will be a valuable addition to our Confo technology and gives us an outstanding toolbox for GPCR structure-based drug discovery. We congratulate Jan for the success of this novel technology and are grateful to VIB for entrusting its use to Confo Therapeutics.”

“We are truly excited to expand our close relationship with the Confo Therapeutics team via this license agreement to further strengthen Confo Therapeutics’ technology platform” said Dr. Carla Snoeck, Manager New Ventures at VIB. “This agreement bears testimony to the mutually fruitful partnership established with Confo Therapeutics since its inception as a VIB-VUB spin-off.


Publication

Questions from patients
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Jan Steyaert
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