psWang Linker Peptide Synthesis Avoids Reprotection

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Solution Overview

Problem

Convergent peptide synthesis methods require additional steps for reprotection of the C-terminal COOH of the C-terminal fragment after solid phase peptide synthesis, leading to inefficiencies and low yields, especially when using Wang resin, which results in unprotected C-terminal fragments incompatible for subsequent coupling reactions.

Innovation Solution

The use of a psWang linker during solid phase peptide synthesis allows for the isolation of the C-terminal fragment with a protected C-terminal COOH, eliminating the need for reprotection and enabling efficient liquid phase coupling of N-terminal and C-terminal fragments, as demonstrated with the synthesis of liraglutide.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If Wang resin is used for solid phase peptide synthesis of the C-terminal fragment, then the synthesis can be completed, but the C-terminal COOH is obtained in unprotected form requiring additional reprotection steps

Engineering Contradiction:

Improveease of C-terminal fragment synthesisVSAvoidcomplexity of synthesis process

Core Design Contradiction:

Ease of manufactureVSDevice complexity

Solution Approach 1:

The psWang linker is pre-installed on the resin before C-terminal fragment synthesis, so that upon cleavage the C-terminal COOH is automatically protected. This preliminary setup eliminates the need for subsequent reprotection steps, directly resolving the contradiction between ease of manufacture and process complexity

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The psWang linker acts as an intermediary protecting group that is automatically transferred to the C-terminal COOH during resin cleavage. This intermediary mechanism provides the protecting group function without requiring separate reprotection operations, reducing process complexity while maintaining ease of manufacture

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If additional reprotection steps are added to protect C-terminal COOH after SPPS, then the fragment becomes compatible for liquid phase coupling, but the process time and isolation steps increase

Engineering Contradiction:

Improvecompatibility for coupling reactionVSAvoidtime for reprotection and isolation

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The protecting group is installed in advance via the psWang linker configuration before the coupling step. The C-terminal fragment is pre-prepared with protected COOH functionality, eliminating the need for time-consuming reprotection and isolation steps immediately before coupling, thus maintaining reliability while reducing time loss

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The use of psWang linker enables continuous workflow where the C-terminal fragment is cleaved with protection already in place, allowing immediate progression to liquid phase coupling without interruption for reprotection. This continuous action eliminates idle time between synthesis and coupling steps

Inventive Principle:

Principle #20Continuity of useful action

3Ease of manufacture

If conventional Wang resin is used, then standard SPPS can be performed, but additional isolation and purification steps are required after reprotection

Engineering Contradiction:

Improveease of SPPS procedureVSAvoidoverall synthesis efficiency

Core Design Contradiction:

Ease of manufactureVSProductivity

Solution Approach 1:

The psWang linker is pre-configured to provide automatic protection upon cleavage, so the C-terminal fragment emerges ready for coupling without requiring separate reprotection and purification cycles. This preliminary setup maintains ease of SPPS while eliminating productivity-reducing steps

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The unnecessary reprotection and isolation steps are extracted/removed from the synthesis workflow by using psWang linker. The method takes out the redundant operations that do not add value, leaving only the essential SPPS and coupling steps, thereby maintaining ease of manufacture while improving productivity

Inventive Principle:

Principle #2Taking out (Extraction)

4Ease of operation

If the C-terminal fragment is cleaved with unprotected COOH, then cleavage is simple, but the fragment cannot be directly used in liquid phase coupling without reprotection

Engineering Contradiction:

Improveease of cleavage operationVSAvoiddirect usability for coupling

Core Design Contradiction:

Ease of operationVSAdaptability or versatility

Solution Approach 1:

The psWang linker is pre-installed to automatically protect the C-terminal COOH during cleavage. This preliminary configuration allows simple cleavage operation while simultaneously ensuring the fragment is in the correct protected form for direct coupling, achieving both ease of operation and adaptability

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The psWang linker performs multiple functions: it serves as the attachment point for SPPS and simultaneously provides protecting group functionality upon cleavage. This multi-functionality allows the cleavage step to produce a fragment that is both easily obtained and immediately usable in coupling, satisfying both ease of operation and adaptability requirements

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentEP3405476B1METHOD FOR PREPARATION OF PEPTIDES WITH psWANG LINKER

Publication Date: 2022.05.18 POLYPEPTIDE LAB HLDG (PPL) AB

AI summary

The invention discloses a method for the preparation of a peptide by liquid phase coupling of two fragments, an N-terminal fragment and a C-terminal fragment of the desired peptide, wherein the C-terminal fragment is protected on its C-terminal COOH by a psWang linker; the method is demonstrated with liraglutide wherein the C-terminal fragment carries the Palmitoyl-Glu-OtBu residue on the Lys.