Engineered Adenylate Kinase Enzymes for Cyclic Dinucleotide Production
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Solution Overview
Problem
There is a need for improved methods to generate cyclic dinucleotides, particularly non-natural cyclic dinucleotides, for enhanced cancer therapies that stimulate immunity through the STING pathway, as existing methods are inefficient and lack industrial process scalability.
Innovation Solution
Engineered adenylate kinase (AdK) enzymes with specific polypeptide sequences and substitutions are developed to produce nucleoside triphosphate substrates, enabling the production of cyclic dinucleotides and non-natural cyclic dinucleotides under industrial conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If existing methods are used to generate cyclic dinucleotides, then the process can be performed, but the efficiency is low and industrial process scalability is lacking
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues in the adenylate kinase enzyme structure (specifically positions 34, 35, 51, 76, 119, 138, 172, and 202) to create engineered variants with improved catalytic activity. These structural parameter modifications enable the enzyme to function effectively under industrial process conditions, thereby improving both production efficiency and scalability of cyclic dinucleotide manufacturing
2Productivity
If engineered AdK enzymes with multiple substitutions are used, then the production of cyclic dinucleotides is enhanced, but the enzyme structure becomes more complex
Solution Approach 1:
The patent applies segmentation by dividing the enzyme optimization into discrete amino acid position modifications. Each substitution at positions 34, 35, 51, 76, 119, 138, 172, or 202 can be independently designed and combined, allowing systematic improvement of catalytic activity while maintaining a manageable structural framework based on the wild-type AdK enzyme
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 engineered AdK enzymes enhance the production of cyclic dinucleotides, improving cancer therapy efficacy by stimulating the immune response through the STING pathway, offering improved scalability and efficiency in industrial processes.
Implementation Method 1
cyclic dinucleotides may be generated enzymatically by cyclization of nucleoside triphosphate substrates
Data Source
AI summary
The present invention provides engineered adenylate kinase (AdK) enzymes, polypeptides having AdK activity, and polynucleotides encoding these enzymes, as well as vectors and host cells comprising these polynucleotides and polypeptides. Methods for producing AdK enzymes are also provided. The present invention further provides compositions comprising the AdK enzymes and methods of using the engineered AdK enzymes. The present invention finds particular use in the production of pharmaceutical compounds.