Chimeric Polypeptides Stabilize GPCR Conformations
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Solution Overview
Problem
Current drug discovery methods for GPCRs face challenges due to conformational flexibility, making it difficult to stabilize receptors in therapeutically relevant conformations, which hampers the identification of effective compounds and increases the risk of undesirable side effects.
Innovation Solution
The development of chimeric polypeptides that fuse a GPCR with a conformation-selective binding domain, such as an immunoglobulin single variable domain, to stabilize the receptor in active or inactive conformations, thereby increasing the affinity for conformation-selective ligands and facilitating more effective drug screening.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional biochemical or cell based screening methods are used on GPCRs in their basal conformation, then the screening process is simple and straightforward, but the identified compounds may not be effective because the basal conformation does not correspond to the druggable conformation
Solution Approach 1:
The patent introduces a conformation-selective binding domain as an intermediary component that specifically binds to and stabilizes the druggable conformation of the GPCR. This binding domain acts as a mediator between the screening system and the GPCR, ensuring that only the therapeutically relevant conformation is presented to potential drug candidates during screening, thereby resolving the contradiction between screening simplicity and compound effectiveness
Solution Approach 2:
The patent changes the conformational parameter of the GPCR by fusing it with a conformation-selective binding domain that locks the receptor in a specific active or inactive conformation. This parameter change ensures that the GPCR maintains the druggable conformation throughout the screening process, improving the reliability of compound identification while managing the added complexity through rational design
2Reliability
If GPCRs are stabilized in a specific conformation using conformation-selective binding domains, then the affinity for conformation-selective ligands is increased, but the structural complexity of the receptor system increases
Solution Approach 1:
The patent merges the GPCR with a conformation-selective binding domain into a single chimeric polypeptide construct. This merging ensures that the binding domain and GPCR are always present in a defined 1:1 stoichiometry, physically tethered together to stabilize the desired conformation while presenting the full therapeutic potential of the GPCR-ligand interaction, thus resolving the contradiction between increased affinity and structural complexity
3Measurement precision
If chimeric polypeptides with conformation-selective binding domains are used, then the sensitivity and selectivity of drug screening is enhanced, but the complexity of the screening target increases
Solution Approach 1:
The conformation-selective binding domain serves as an intermediary that enhances the sensitivity and selectivity of screening by specifically recognizing and stabilizing the druggable conformation of the GPCR. This intermediary component allows the screening system to distinguish between different conformations with high precision, resolving the contradiction between measurement precision and target complexity
Solution Approach 2:
The patent changes the conformational parameter of the GPCR through fusion with a conformation-selective binding domain, creating a stabilized chimera that presents a more precise and selective target for screening. This parameter change improves measurement precision by ensuring that only the relevant conformation is available for ligand binding, while the added complexity is managed through the well-defined structure of the chimera
Data Source
AI summary
The present invention relates to novel polypeptides and their use for screening and drug discovery. More specifically, the invention provides chimeric polypeptides comprising a membrane protein, in particular a GPCR, fused to a binding domain, wherein the binding domain is directed against and/or specifically binds to said membrane protein. In particular, the chimeric polypeptides of the invention are single proteins wherein, in an intramolecular reaction, the binding domain stabilizes the membrane protein in a conformation of interest. Also provided are nucleic acid sequences encoding such chimeric polypeptides, cells capable of expressing such chimeric polypeptides as well as cellular compositions derived thereof. Also envisaged are screening methods for compounds using the chimeric polypeptides of the invention.