Peptide Secondary Structure Stabilization via Thioether Crosslinking

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Solution Overview

Problem

Current methods for stabilizing α helix peptides are ineffective due to instability in aqueous solutions and challenges in incorporating special amino acids into in vitro display systems, limiting their potential for high inhibitory activity and selectivity.

Innovation Solution

The use of genetic code reprogramming and a special peptide synthesizing technology to introduce a special amino acid with a sulfanyl group, allowing for spontaneous crosslinking and formation of a thioether bond, stabilizing the peptide's secondary structure during translational synthesis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If chemical synthesis is used to incorporate special amino acids and form covalent bonds, then the α helix secondary structure can be stabilized, but the process complexity and difficulty of incorporation into in vitro display systems increase

Engineering Contradiction:

Improveα helix secondary structure stabilityVSAvoidprocess complexity

Core Design Contradiction:

Stability of the object's compositionVSDevice complexity

Solution Approach 1:

The peptide system itself performs the crosslinking function through the spontaneous reaction between the sulfanyl group and the electrophilic group during translation, eliminating the need for external chemical catalysts or complex post-synthesis modification steps. The amino acid sequence is designed to self-assemble and self-stabilize the α helix structure through intrinsic chemical reactivity.

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The special amino acids with complementary reactive groups (sulfanyl and electrophilic) are pre-incorporated into the peptide sequence at positions that will form the crosslink. The translation system is designed to incorporate these amino acids in the correct positions before the spontaneous crosslinking occurs, ensuring proper spatial arrangement for helix stabilization.

Inventive Principle:

Principle #10Preliminary action

2Stability of the object's composition

If crosslinking is performed using chemical catalysts, then covalent bonds can be formed to support the helix structure, but the method depends entirely on chemical synthesis

Engineering Contradiction:

Improvehelix structure supportVSAvoidchemical synthesis dependency

Core Design Contradiction:

Stability of the object's compositionVSEase of manufacture

Solution Approach 1:

The patent replaces the chemical synthesis system (requiring external catalysts and complex procedures) with a biological translation system. The ribosome and translation machinery naturally incorporate the special amino acids into the peptide chain, and the subsequent spontaneous crosslinking occurs without external chemical catalysts, replacing mechanical/chemical intervention with biological self-organization.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The translation system performs multiple functions: it incorporates standard amino acids, incorporates the special amino acids with reactive groups at specific positions, and the resulting peptide spontaneously crosslinks to stabilize its structure. This multi-functional approach eliminates the need for separate chemical synthesis and crosslinking steps.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Device complexity

If short-chain peptides are used based on amino acid sequence information, then the structure can be simple, but the peptides are exposed to solvent and cannot maintain their structure

Engineering Contradiction:

Improvepeptide structure simplicityVSAvoidstructure maintenance in aqueous solution

Core Design Contradiction:

Device complexityVSStability of the object's composition

Solution Approach 1:

The patent creates a composite structure by incorporating two types of functional groups (sulfanyl and electrophilic) within the same peptide molecule. These groups form intramolecular crosslinks that create a composite architecture combining the simplicity of short-chain peptides with the structural stability of crosslinked networks, maintaining rigidity while preserving sequence-based design simplicity.

Inventive Principle:

Principle #40Composite materials

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach results in peptides with enhanced stability, affinity, and selectivity, enabling the creation of libraries with improved cell membrane permeability and physiological activity.

Implementation Method 1

having the crosslinked structure formed through a thioether bond between the side chain of the special amino acid residue and the sulfanyl group

Methodology Applied

Scientific EffectSubstitution reaction: Chemical Bonding

Data Source

PatentUS10435439B2Peptide with safer secondary structure, peptide library, and production methods for same

Publication Date: 2019.10.08 THE UNIV OF TOKYO

AI summary

An object of the invention is to provide a peptide having a stabilized secondary structure.The present invention provides a peptide having a secondary structure stabilized by a crosslinked structure and containing at least one combination of a special amino acid of the formula (I):(wherein, (A) represents a single bond or a linking group having, in the main chain thereof, from 1 to 10 atoms;(B) represents a group containing at least one π bond;(C) represents a hydrogen atom or an alkyl group which may be substituted with a substituent; and X represents a group substitutable by a substitution reaction with a sulfanyl group) and an amino acid having, in the side chain thereof, a sulfanyl group; and having the crosslinked structure formed through a thioether bond between the side chain of the special amino acid residue and the sulfanyl group.