Unleashing the Therapeutic Potential of GPCRs

GPCRs are critical proteins in health and disease

G protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in the body. They play a key role in a broad range of biological processes by binding to a wide variety of signaling molecules, yet they share a common architecture. GPCRs are comprised of seven transmembrane (TM) helices that span the cell membrane and intervening loops that are presented towards either the extracellular (EC) or intracellular (IC) environments. Agonists bind to GPCRs at an EC-facing binding pocket and initiate conformational changes that are propagated to the IC loops. This subsequently triggers downstream signaling via G-proteins or G-protein-independent pathways.

GPCR ligands often preferentially activate particular downstream pathways (signaling bias) and thus illicit different biological effects. This functional plasticity can be attributed to the intrinsic structural flexibility of GPCRs and the ability of signaling molecules to recognize and stabilize specific conformations.

GPCRs are a diverse group of receptors that share a common architecture.
When an agonist binds to a GPCR, conformational changes are induced that subsequently trigger downstream signaling via G-proteins or via G-protein-independent pathways.

The Challenge

Approximately 30% of all drugs currently on the market target GPCRs. However, more than 50% of all GPCR targets in the body have not been successfully drugged despite being strongly implicated in numerous disease states, leaving vast untapped potential for future exploration. Much of the difficulty involved in drugging GPCRs can be attributed to the limited chemical space that can be covered with state-of-the-art methods, and/or the fact that unmodified GPCRs are difficult to study due to their innate conformational flexibility.

The Solution

The Confo® technology uses conformationally selective VHH antibodies – ConfoBodies® – to stabilize GPCRs in disease-relevant conformations, allowing precision fragment-based drug discovery to find novel medicines with optimal properties.

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