G Protein Peptidomimetics Stabilize Active GPCR Conformations
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Solution Overview
Problem
Current methods for stabilizing G protein-coupled receptors (GPCRs) in active conformational states are challenging due to their instability and difficulty in isolating and purifying them, hindering the identification of agonists or inverse agonists, especially for peptide receptors, which are less tractable using traditional drug discovery approaches.
Innovation Solution
Development of G protein peptidomimetics derived from the α5 helix with specific amino acid substitutions and stabilizing staples that increase agonist affinity to GPCRs, allowing for the stabilization of GPCRs, such as the dopamine (D1) receptor, in an active state, facilitating fragment-based screening for drug discovery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If traditional cell-based assay systems and high-throughput screening are used for GPCR drug discovery, then existing GPCRs can be screened, but peptide receptors and newer targets prove less tractable and difficult to identify agonists or inverse agonists
Solution Approach 1:
The patent introduces G protein peptidomimetics as intermediary molecules that bind to GPCRs and stabilize them in active conformations. These peptidomimetics act as mediators between the receptor and the screening process, enabling the identification of agonists and inverse agonists that traditional methods cannot detect, particularly for peptide receptors.
Solution Approach 2:
The invention changes the conformational parameter of GPCRs by stabilizing them in active states using peptidomimetics. This parameter change enables traditional screening methods to successfully identify agonists and inverse agonists for previously intractable targets like peptide receptors, thereby improving both adaptability and productivity.
2Measurement precision
If biophysical assays and structural techniques are applied to GPCRs, then structure determination may be achieved, but GPCRs are highly unstable when extracted from cell membranes making them difficult to isolate and purify
Solution Approach 1:
The G protein peptidomimetics serve as intermediary stabilizing agents that bind to GPCRs during isolation and purification processes. This intermediary binding maintains the receptor's structural integrity and stability, enabling successful purification and subsequent structure determination using biophysical assays and structural techniques.
Solution Approach 2:
The patent applies prior cushioning by pre-stabilizing GPCRs with peptidomimetics before extraction from cell membranes. This preemptive stabilization prevents degradation and instability during the isolation and purification processes, making structure determination feasible.
3Stability of the object's composition
If GPCRs are stabilized in active conformational states using existing methods, then some structural information can be obtained, but the difficulty remains in stabilizing GPCRs in the appropriate conformation to identify weak binders with desired pharmacology
Solution Approach 1:
The G protein peptidomimetics act as intermediary molecules that specifically stabilize GPCRs in active conformations. This stable active conformational state serves as a reliable platform for identifying weak binders with desired pharmacology, including agonists and inverse agonists, that would otherwise be difficult to detect.
Solution Approach 2:
The invention changes the conformational parameter of GPCRs to a stable active state through peptidomimetic binding. This parameter change enables reliable identification of weak binders with specific pharmacological properties, improving both conformational stability and the reliability of drug discovery outcomes.
Data Source
AI summary
The present invention relates to G protein peptidomimetics capable of stabilizing a GPCR in an active conformational state. The G protein peptidomimetics are derived from the G protein epitope interacting with the GPCR, in particular from the C-terminus of the as helix comprising the amino acid sequence FNDCRDIIQRMHLRQYELL (SEQ ID NO:117). The invention further provides complexes of the G protein peptidomimetics and a GPCR, fusion polypeptides of a GPCR and the G protein peptidomimetics and compositions comprising the same. Further disclosed herein are uses of the G protein peptidomimetics, complexes, fusion polypeptides and compositions for determining the structure of the GPCR conformer and for screening for compounds capable of specifically binding to the GPCR conformer.