Cyclic Angiotensin Peptides Thioether Bridge Stability

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

The limited stability of small, linear angiotensin peptides restricts their medical and industrial applications due to rapid degradation, which affects their therapeutic efficacy and duration of action.

Innovation Solution

Introduction of a thioether-ring structure between amino acids corresponding to positions 4 and 7 in angiotensin peptides, such as Ang(1-8) and Ang(1-7), enhances proteolytic resistance without compromising biological activity, allowing for more stable and effective therapeutic agents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If linear angiotensin peptides are used, then they maintain simple structure and biological activity, but they exhibit rapid degradation and limited stability

Engineering Contradiction:

Improvepeptide stabilityVSAvoidpeptide structure complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The peptide is divided into two segments: a linear N-terminal portion (residues 1-3) and a cyclic C-terminal portion (residues 4-7) connected by a flexible linker. This segmentation allows the molecule to combine the stability of cyclic structures with the biological activity of the linear sequence, resolving the contradiction between stability and structural simplicity

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The cyclic structure containing residues 4-7 is nested within the larger peptide framework, with the flexible linker connecting it to the N-terminal residues. This nested arrangement protects the critical C-terminal region from degradation while maintaining overall peptide function, addressing the stability-complexity trade-off

Inventive Principle:

Principle #7Nested doll (Nesting)

2Duration of action of moving object

If linear angiotensin peptides are used, then they are easy to synthesize and administer, but they have short half-life and require frequent dosing

Engineering Contradiction:

Improvetherapeutic durationVSAvoidsynthesis and administration ease

Core Design Contradiction:

Duration of action of moving objectVSEase of manufacture

Solution Approach 1:

The flexible linker in the peptide structure provides dynamic conformational adaptability, allowing the molecule to adjust its shape for optimal receptor binding while maintaining the stable cyclic core. This dynamic feature extends therapeutic duration without requiring complex synthesis procedures, as the flexibility is inherent in the peptide bond structure

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The invention changes the structural parameter of the peptide by introducing a cyclic motif, which fundamentally alters the degradation kinetics and half-life of the molecule. This parameter change extends therapeutic duration while the modular design keeps synthesis relatively straightforward

Inventive Principle:

Principle #35Parameter changes

3Reliability

If cyclic structures are introduced to improve stability, then proteolytic resistance increases, but structural complexity and synthesis difficulty increase

Engineering Contradiction:

Improveproteolytic resistanceVSAvoidcyclic structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Only the C-terminal region (residues 4-7) is cyclized to provide local proteolytic resistance, while the N-terminal region remains linear to maintain biological activity. This localized modification achieves the desired reliability without requiring complete structural cyclization, thus reducing overall complexity

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS8835375B2Cyclic angiotensin analogs

Publication Date: 2014.09.16 APPLIED NANOSYST

AI summary

The invention relates to analogs of angiotensins, in particular to cyclised analogs having Ang(1-8) agonistic or antagonistic activity and to cyclised Ang(1-7) analogs with agonistic or antagonistic activity and displaying improved proteolytic resistance compared to their linear counterparts. Provided is a cyclic angiotensin peptide analog comprising a thioether-bridge linkage between the amino acids corresponding to positions Tyr4 and Pro7 in naturally occurring Angiotensin. Also provided is the use of analogs in therapy, for example hypertension.