Nonpeptidic Cross-Linked Peptides for Metabolic Stability

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Solution Overview

Problem

Current methods for developing cross-linked peptides face challenges in achieving metabolic stability, bioavailability, receptor selectivity, and minimizing side effects due to enzymatic cleavage and structural flexibility, limiting their pharmacological applications.

Innovation Solution

A novel cross-linked peptide with a nonpeptidic cross-linked structure is synthesized using a specific organic compound, allowing for peptide elongation in a liquid phase and cross-linking at any site, enabling optional substitutions and alterations in the cross-linked structure, thereby enhancing resistance to peptidases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a peptide is used as a medicinal product, then it can treat diseases correlated with peptides, but it is decomposed by peptidases under physiological conditions, resulting in low metabolic stability

Engineering Contradiction:

Improvemetabolic stabilityVSAvoiddecomposition by peptidases

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent introduces a nonpeptidic cross-linked structure that combines peptide sequences with non-peptide moieties (such as hydrocarbon chains, heteroatom-containing groups, or aromatic rings) to create a hybrid molecular architecture. This composite structure provides resistance to peptidase degradation while maintaining biological activity, directly resolving the contradiction between therapeutic efficacy and metabolic stability

Inventive Principle:

Principle #40Composite materials

Solution Approach 2:

The patent modifies the chemical parameters of the peptide by introducing cross-linked structures with specific properties (hydrophobicity, rigidity, steric bulk) that alter the peptide's interaction with peptidases. These parameter changes reduce enzymatic recognition and cleavage, thereby improving metabolic stability without sacrificing therapeutic function

Inventive Principle:

Principle #35Parameter changes

2Reliability

If a peptide is used as a medicinal product, then it can treat diseases, but absorption after ingestion is poor due to relatively large molecular weight

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidabsorption after ingestion

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent divides the peptide structure into segments connected by cross-linked moieties, creating a modular architecture that reduces effective molecular weight for absorption purposes while maintaining overall therapeutic function. The segmented structure allows better penetration through biological membranes

Inventive Principle:

Principle #1Segmentation

3Reliability

If a peptide is used as a medicinal product, then it can treat diseases, but excretion through liver and kidney is fast

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidexcretion rate

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The nonpeptidic cross-linked structure creates a hybrid molecule that combines peptide pharmacophores with non-peptide carriers having different pharmacokinetic properties. This composite design slows renal filtration and hepatic metabolism, extending the duration of action while preserving therapeutic efficacy

Inventive Principle:

Principle #40Composite materials

4Reliability

If a peptide is used as a medicinal product, then it can treat diseases, but undesired side effects occur in non-targeted tissues and organs due to structural flexibility and wide distribution of receptors

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidside effects in non-targeted tissues

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces rigid cross-linked structures at specific locations within the peptide sequence to create localized conformational constraints. This local structural control maintains the pharmacologically active conformation while reducing overall flexibility, thereby enhancing receptor selectivity and minimizing off-target effects

Inventive Principle:

Principle #3Local quality

5Reliability

If a peptide has a controlled conformation to improve receptor affinity, then metabolic stability and selectivity increase, but synthesis complexity increases

Engineering Contradiction:

Improvereceptor selectivity and metabolic stabilityVSAvoidsynthesis complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent incorporates cross-linked structures during the peptide synthesis process itself, rather than requiring post-synthesis cyclization or conformational locking steps. This preliminary action integrates conformational control into the synthesis workflow, reducing overall complexity while achieving the desired controlled conformation

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS10654891B2Cross-linked peptides containing non-peptide cross-linked structure, method for synthesizing cross-linked peptides, and novel organic compound used in method

Publication Date: 2020.05.19 JITSUBO CO LTD

AI summary

The purpose of the present invention is to provide a cross-linked peptide containing a novel non-peptide cross-linked structure, and a method for synthesizing the same. A cross-linked peptide having a novel non-peptide cross-linked structure, a useful intermediate for synthesizing the cross-linked peptide, and a method for synthesizing the novel cross-linked peptide and the intermediate are provided. The cross-linked peptide is characterized by having an —NR— bond in the cross-linked structure. By using the method for synthesizing the cross-linked peptide, a cross-link can be freely designed and an change can be freely made to a cross-link.