Chimeric Peptide Antagonist for GPCR135 Selectivity

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Solution Overview

Problem

Current technologies lack selective antagonists for GPCR135 and/or GPCR142 over LGR7, which are crucial for therapeutic targeting due to the potential activation of LGR7 by relaxin-3, impacting physiological functions such as drinking and other processes.

Innovation Solution

Development of chimeric polypeptides like R3(BΔ23-27)R/I5, comprising a relaxin-3 B-chain with a C-terminal truncation and an INSL5 A-chain, which acts as a high-affinity antagonist for GPCR135 with minimal affinity for LGR7, thereby selectively inhibiting GPCR135 activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If relaxin-3 is used to activate GPCR135, then GPCR135-mediated responses are activated, but LGR7 is also activated causing unwanted physiological effects

Engineering Contradiction:

ImproveselectivityVSAvoidoff-target activation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The relaxin-3 peptide is divided into two separate chains (A-chain and B-chain) that are linked by disulfide bonds. By segmenting the peptide structure and selectively modifying the B-chain through C-terminal truncation, the invention achieves selective activation of GPCR135 while avoiding LGR7 activation, thus resolving the selectivity contradiction

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention applies local quality modification by specifically truncating the C-terminal region of the B-chain (residues 23-27) while keeping the A-chain intact. This localized structural change alters the peptide's binding properties to achieve high affinity for GPCR135 while eliminating affinity for LGR7, resolving the contradiction between activation efficacy and selectivity

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If selective antagonists are developed for GPCR135, then therapeutic targeting is improved, but current technologies lack such selective agents

Engineering Contradiction:

Improvetherapeutic applicabilityVSAvoidselectivity

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The invention creates a composite peptide structure by combining the A-chain of relaxin-3 with a modified B-chain that has C-terminal truncation. This composite structure (R3(BΔ23-27)R/I5) provides both high affinity binding to GPCR135 and selective antagonistic activity, enabling reliable therapeutic targeting without cross-reactivity with LGR7

Inventive Principle:

Principle #40Composite materials

3Reliability

If chimeric polypeptides with modified B-chain are created, then selectivity for GPCR135 is achieved, but peptide structure complexity increases

Engineering Contradiction:

ImproveselectivityVSAvoidpeptide structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention applies the extraction principle by removing specific amino acid residues (C-terminal truncation of residues 23-27 from the B-chain) to create the modified peptide structure. This removal simplifies the overall structure compared to full-length relaxin-3 while achieving the desired selectivity, as the truncated region is precisely extracted to eliminate LGR7 binding capability

Inventive Principle:

Principle #2Taking out (Extraction)

Data Source

PatentEP2129359B1Chimeric peptide antagonist for GPCR135 or GPCR142

Publication Date: 2012.03.14 JANSSEN PHARMA NV

Figure 1A~1C
Figure 2A~2C
Figure 3A~3B

AI summary

The chimeric polypeptide R3(BΔ23-27)R/I5 is described, which is a high- affinity antagonist for GPCRl 35 and GPCRl 42 over LGR7.