Protein structures for health: Structural biology of therapeutic membrane proteins as a starting point for effective rational drug design.

Drugs targeting GPCRs accounted for over EURO60bn of the pharmaceutical industry's annual sales in 2009, about 25% of the worldwide pharmaceutical market in that year. Ion-channels and transporters represent the second largest class of drugable targets and it is expected that membrane proteins will continue to constitute the majority of drug targets in the future, because it is usually at the membrane level (receptors, channels, transporters) that specificity in signal transduction is achieved.

With the overall outcome of the pharmaceutical industry in terms of new marketed drugs declining, one of the big hopes in the sector now resides in structure-based drug development. Unfortunatly, structural knowledge of membrane proteins has so far proven extremely difficult to generate, essentially because membrane proteins are difficult to handle outside of their natural lipid environment. In phase I of 3D4Health, we demonstrated the power of Xaperones to generate diffracting quality crystals of the most challenging membrane proteins including GPCRs and MDRs. Xaperones are single domain antigen binding fragments from heavy-chain only antibodies from Camelids. By rigidifying flexible regions and obscuring aggregative surfaces, Xaperone complexes warrant conformationally uniform samples that are key to protein structure determination by X-ray crystallography. An unanticipated but important finding was that xaperones can selectively stabilize distinct conformers of conformationally rich membrane proteins. Some of these conformational selective Xaperones against GPCRs act as antagonists, others behave as allosteric activators and increase the affinity for agonists at the orthosteric site, illustrating their therapeutic potential.

The goal of 3D4Health phase II will be to turn this technology platform into a robust pipeline for generating Xaperones that stabilize unique therapeutic conformations of many therapeutic targets and to structure these activities into a new spin-off company according to two possible business models: a platform company that provides services in structural biology or a fully integrated drug discovery company focussed on small molecules.

The coming two years, we will focus on 4 key objectives. First, we want to solve more structures of GPCRs and (ion) channels by use of Xaperone-assisted crystallography as eye-catchers for the pharmaceutical industry and to proof the broad applicability of our technology. Second, we want to streamline Xaperone discovery strategies that are independent on purified protein. Third, we will explore the potency of allosteric modulators to improve high throughput screening exepriments and finally, we want to implement the most appropriate business model. The focus of the future company will largely depend on the strenght of the IP we can generate in the coming two years, but also on the availibility of (venture) capital, the investors confidence and the quality of the future management.