Modified Relaxin B-Chain Peptides for RXFP1 Activation

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Solution Overview

Problem

Current Relaxin-2 peptides are difficult to synthesize and purify due to their complex heterodimeric structure, leading to low yields and high costs, and existing simplified analogues have insufficient capacity to activate the RXFP1 receptor effectively.

Innovation Solution

Development of modified Relaxin peptides with shorter sequences and improved solubility and stability, such as peptide B7-33 C11.23S, AcB7-33 C11.23S, and KKKK(AcB7-29 C11.23S, which demonstrate enhanced ability to activate the RXFP1 receptor with lower EC50 values and improved plasma stability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If simplified Relaxin B-chain analogues are used, then synthesis difficulty is reduced, but RXFP1 receptor activation capacity is insufficient

Engineering Contradiction:

Improvesynthesis difficultyVSAvoidRXFP1 receptor activation capacity

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent introduces specific amino acid substitutions at critical positions (K15, R17, I20, M24, L26, I27, L29, K32) within the B-chain sequence to locally enhance receptor binding affinity and activation capacity, while maintaining the overall simplified structure for ease of synthesis

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically varies amino acid residues at key positions to optimize the balance between synthesis feasibility and biological activity, achieving improved EC50 values while maintaining simplified peptide structures that are easier to manufacture than native Relaxin-2

Inventive Principle:

Principle #35Parameter changes

2Reliability

If native Relaxin-2 heterodimeric structure is used, then RXFP1 receptor activation capacity is high, but synthesis and purification are difficult with low yields

Engineering Contradiction:

ImproveRXFP1 receptor activation capacityVSAvoidsynthesis and purification difficulty

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent extracts only the essential B-chain component required for RXFP1 activation, discarding the complex A-chain and heterodimeric structure, thereby simplifying synthesis and purification while retaining sufficient biological activity through optimized B-chain sequences

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent creates simplified peptide analogues that copy only the critical functional elements of the native Relaxin-2 B-chain needed for receptor activation, using truncated and modified sequences that replicate essential binding interactions without requiring the full heterodimeric structure

Inventive Principle:

Principle #26Copying

3Ease of manufacture

If existing simplified analogues are used, then production cost is reduced, but therapeutic efficacy is insufficient

Engineering Contradiction:

Improveproduction costVSAvoidtherapeutic efficacy

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent combines multiple amino acid modifications within the B-chain sequence to create composite peptide structures that integrate both cost-effectiveness and enhanced therapeutic efficacy, achieving improved EC50 values while maintaining simplified production processes

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS10988524B2Modified relaxin B chain peptides and their therapeutic use

Publication Date: 2021.04.27 SANOFI SA(FR)

AI summary

Provided is a biologically active single chain Relaxin peptide having the following formula (I): Nter-X-(E)a-X10-E-G-R-E-X15-V-R-X18-X19-I-X21-X22-E-G-X25-S-X27-X28-X29-X30-R-(X32)b-(X33)c-(X34)d-NH2-Cter. Also provided is a pharmaceutical composition comprising at least one peptide of the invention, or a pharmaceutically acceptable salt or a solvate thereof. Further provided is the peptide, a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition for use as a medicament.