With its unique antibody-based technology, Confo Therapeutics aims to overcome the current limitations of GPCR drug discovery in order to fully realize the potential of GPCRs as drug targets.
Confo Technology Suite
Our drug discovery engine uses advanced antibody technology, ConfoBodies,
to enable superior and more efficient drug discovery for dynamic membrane proteins in their natural environment.
A ConfoBody is a single-domain antibody (VHH), generated using our proprietary processes, that binds to and stabilizes the protein in its therapeutically relevant conformation, for example in the agonist-bound active state. Our team has over 10 years of experience in ConfoBody discovery, employing a suite of VHH discovery techniques.
An active state-specific ConfoBody does not bind to the GPCR in its basal state. In the presence of an agonist, the ConfoBody binds to and stabilizes the agonist-GPCR complex.
[left]: Due to their unique shape, ConfoBodies recognize specific structural folds on native proteins, making them the ideal tool to stabilize disease-relevant conformational states of membrane proteins.
[right]: ConfoBodies can also stabilize protein complexes, such as the active GPCR–G-protein complex.
We have developed highly sensitive and selective screening assays which enable us to focus our screening efforts on the therapeutically relevant confirmation with ConfoBodies. We use ConfoBodies and MegaBodies® to stabilize the protein target in its disease-relevant state for structure-based drug design.
ConfoScreen® is our suite of ConfoBody®-based screening methods
The ConfoBody stabilizes the GPCR in its active conformation and, by doing so, improves the chances of identifying ligands that are conformationally selective. For example, an active-state-specific ConfoBody increases sensitivity for agonists by stabilizing the agonist–GPCR complex.
As a result, our proprietary ConfoScreen methods are highly sensitive, enabling the identification of smaller – and hence more difficult to detect – chemical starting points, including fragments (<300 MW).
[Basal GPCR]: In the absence of a ConfoBody, the GPCR resides mainly in its basal, ‘inactive’ state.
[Active GPCR]: An active state-specific ConfoBody stabilizes the agonist-GPCR complex, resulting in a higher binding signal of agonists in the presence of the ConfoBody. This provides an increased screening sensitivity especially for the active conformation.
We have also developed ConfoSensor®, a new proprietary screening method whereby conformation-specific ConfoBodies are used as biosensors to detect conformational changes, for example when an agonist ligand binds.
[Basal GPCR]: In the absence of an agonist ligand, an active state-specific ConfoBody hardly binds to the GPCR
[Active GPCR]: When an agonist ligand or an agonist fragment binds, the GPCR will move to its active state and the ConfoBody will be recruited
Our proprietary universal G-protein-specific ConfoBodies can also be used in ligand binding ConfoScreen assays and in ConfoSensor as universal screening tools instead of, or in addition to, GPCR-specific ConfoBodies. The G-protein-specific ConfoBodies can also specifically detect signaling pathways upon activation, to better elucidate the downstream pharmacology of a GPCR of interest.
ConfoStructure™ enables structure-based drug discovery to support the rational design of optimal compounds
As shown in multiple, frequently cited scientific papers, ConfoBodies® are invaluable tools for determining three-dimensional structures of target proteins in the conformation of interest for example the active state. They can be used to stabilize membrane proteins for crystallization and X-ray studies, or for single-particle cryogenic electron microscopy (cryo-EM).
We have acquired an exclusive license to the MegaBody™ technology, a new ConfoBody-based scaffold that maintains the conformational selectivity of the parent ConfoBody while providing more mass and structural features for use in high-resolution cryo-EM. MegaBodies™ trap protein conformations, influence particle orientation, serve as a handle for three-dimensional image reconstruction and increase the size of the protein complex thus making GPCRs more amenable to study via Cryo-EM.
A MegaBody™ (right) is a large and rigid protein, consisting of a functional ConfoBody (left) grafted onto a larger protein scaffold. MegaBody™ is a VIB trademark.
Confo Therapeutics is rapidly building up internal capabilities in structural biology and has secured access to the VUB–VIB cryo-EM facility. Our aim is to determine three-dimensional structures (apo and ligand-bound) of target GPCRs in their conformation of interest and to elucidate how compounds bind to GPCRs in order to support structure-based drug design
Precision fragment-based drug design
At Confo we have built a fragment collection that is diverse and well poised for GPCR drug discovery. In addition, our proprietary ConfoScreen® screening methods are highly sensitive, enabling us to effectively detect low molecular weight fragment hits as starting point for our drug discovery programs.
The appeal of fragment-based screening (MW ≤ 300) is driven by a couple of factors:
- “Fragment Space” (106) is vastly smaller than “Chemical Space” (1060), and hence the diversity in fragment space can be more effectively probed
- for complex targets such as GPCRs, hit rates for fragment-based screening appear to be higher than conventional high-throughput screening approaches, provided a sensitive fragment screening method is utilised
We exploit ConfoStructures using structure-based drug design approaches, to rapidly and efficiently improve µM chemical starting points to nM affinity lead compounds with excellent drug-like properties.
[Left] Using Confo’s screening technology we can identify diverse fragments that are well poised for GPCR drug discovery
[Right] Based on structural information, the fragment starting points are then elaborated towards high affinity lead compounds