PEG Esters with 3,5-DC-2-HBSA Activators for Peptide Acylation
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Solution Overview
Problem
Current acylation methods for pharmaceutical peptides and proteins face challenges with hydrolytic instability, requiring rigorous control and resulting in low yields and high costs, particularly due to the use of NHS-based acylating agents.
Innovation Solution
Development of novel acylating agents in the form of esters with specific activators like 3,5-DC-2-HBSA and 3,5-DC-2-HDMBSA, which offer improved stability, robustness, and economic advantages by allowing for simpler reaction conditions and reduced agent amounts, facilitating the acylation of amino groups in peptides and proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NHS-based acylating agents are used for acylation of peptides and proteins, then the acylation reaction can proceed, but the process suffers from hydrolytic instability requiring rigorous control and resulting in low yields and high costs
Solution Approach 1:
The patent changes the chemical parameters of the acylating agent by replacing NHS-based agents with novel esters containing specific activators (Chem. 1b or 1c). This parameter change fundamentally alters the hydrolytic stability and reaction characteristics, enabling higher yields and reduced costs while maintaining acylation effectiveness.
Solution Approach 2:
The invention employs readily available starting materials (Chem. 6a or 6b) that can be easily converted into the novel ester acylating agents. These agents are designed to be used in controlled amounts and discarded after single use, eliminating the need for expensive, complex purification and recycling systems associated with NHS-based agents.
2Reliability
If NHS-based acylating agents are used, then acylation can be achieved, but rigorous control is required leading to high costs
Solution Approach 1:
By changing the chemical structure to novel esters with activators Chem. 1b or 1c, the patent reduces the need for rigorous process control. The new agents inherently provide better stability and reactivity characteristics, simplifying manufacturing conditions and reducing costs associated with controlled environments and monitoring.
Solution Approach 2:
The novel ester compounds act as intermediary agents that bridge the starting materials and the final acylated products. These intermediaries are designed to be more stable and easier to handle than NHS-based agents, reducing the need for complex control systems and expensive infrastructure.
3Stability of the object's composition
If conventional acylating agents are used, then the acylation process can be completed, but the agents are hydrolytically unstable
Solution Approach 1:
The patent fundamentally changes the chemical parameters of the acylating agent by introducing novel ester structures with specific activators. This parameter change simultaneously improves hydrolytic stability and maintains reaction efficiency, as the new agents are designed to resist hydrolysis while remaining sufficiently reactive for peptide and protein acylation.
Solution Approach 2:
The invention creates composite molecular structures combining ester linkages with specific activators (Chem. 1b or 1c). These composite structures leverage the stability of ester bonds while incorporating the reactivity needed for efficient acylation, achieving both stability and productivity improvements.
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
The novel acylating agents provide enhanced hydrolytic stability, increased robustness, and cost-effectiveness in the acylation process, leading to higher purity and yield of acylated products with greater flexibility in reaction conditions.
Implementation Method 1
The attachment of one or more substituents to peptides or proteins by acylation of one or more amino groups of the peptide or protein is well-known in the art
Data Source
AI summary
The present invention relates to a novel acylating agent, a method for its preparation, and a method of using it for acylating one or more amino groups of an amino acid, a peptide, or a protein. The novel acylating agent may be a compound which comprises a structural element —HN—(CH2)2-(O—((CH2)2)k-O—(CH2)n-CO—, wherein k is an integer in the range of 1-10, and n is an integer in the range of 1-2, being esterified at its —CO-end to the hydroxy group of 3,5-dichloro-2-hydroxy-benzenesulfonic acid (3,5-DC-2-HBSA). This novel acylating agent has an improved stability. Using this agent the acylation process is improved as regards robustness, as well as improving yield and overall production economy. The novel acylating agent is useful for acylating pharmaceutical peptides and proteins such as GLP-1, insulin, pYY, and amylin. The invention also relates to a number of novel GLP-1 precursor peptides and derivatives in which the two N-terminal amino acids have been deleted.