Thyclotides Oligomers for PNA Solubility and Binding
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Solution Overview
Problem
Peptide nucleic acids (PNAs) face challenges with poor cellular uptake and low aqueous solubility, limiting their applications in biomedical areas, despite efforts to modify their backbone for improved binding properties and stability.
Innovation Solution
Development of oligomers comprising monomer units with specific configurations of tetrahydrofuran rings, enhancing binding affinity and solubility by forming right-handed helices that match DNA and RNA, thereby improving cellular uptake and sequence specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If the backbone of PNAs is modified with non-polar cyclopentane rings to rigidify the structure, then binding affinity to complementary nucleic acids increases, but water solubility deteriorates
Solution Approach 1:
The patent applies local quality by introducing polar groups at specific positions of the cyclopentane ring structure while maintaining the rigidifying effect. The modification is localized to specific carbon positions (e.g., 2,6-dicarboxylic acid groups at positions 3 and 4) rather than throughout the entire structure, allowing the backbone to maintain rigidity for binding affinity while adding polarity locally to improve water solubility.
Solution Approach 2:
The patent creates composite structures by combining the hydrophobic cyclopentane ring framework with hydrophilic polar groups (carboxylic acid, hydroxyl, or amine groups). This composite approach integrates both hydrophobic and hydrophilic characteristics within the same monomer unit, enabling the PNA to achieve both high binding affinity through the rigid cyclopentane core and improved solubility through the polar substituents.
2Quantity of substance
If chemical modifications are made to the PNA backbone to improve water solubility and bio-compatibility, then solubility increases, but binding affinity and sequence specificity decrease
Solution Approach 1:
The patent applies local quality by introducing polar groups at specific positions of the cyclopentane ring structure while maintaining the rigidifying effect. The modification is localized to specific carbon positions (e.g., 2,6-dicarboxylic acid groups at positions 3 and 4) rather than throughout the entire structure, allowing the backbone to maintain rigidity for binding affinity while adding polarity locally to improve water solubility.
Solution Approach 2:
The patent creates composite structures by combining the hydrophobic cyclopentane ring framework with hydrophilic polar groups (carboxylic acid, hydroxyl, or amine groups). This composite approach integrates both hydrophobic and hydrophilic characteristics within the same monomer unit, enabling the PNA to achieve both high binding affinity through the rigid cyclopentane core and improved solubility through the polar substituents.
3Reliability
If PNAs are used for antisense and antigene applications, then gene expression control is achieved, but cellular uptake remains poor
Solution Approach 1:
The patent applies parameter changes by systematically varying the polarity parameters of the PNA backbone through different substituent groups (carboxylic acid, hydroxyl, amine). These parameter changes in molecular polarity and charge distribution enhance cellular uptake by improving compatibility with cellular membranes and transport mechanisms, while the core cyclopentane structure maintains the binding reliability for gene expression control.
Data Source
AI summary
Disclosed are thyclotides, which are oligomers, each comprising (a) from about 8 to about 25 monomer units of formula (I) and (b) from 0 to about 24 monomer units of formula (II): wherein B is a nucleobase, which can be the same or different at each occurrence, or a pharmaceutically acceptable salt thereof. The thyclotides are soluble in water, bind strongly to complementary DNA and RNA, and are cell permeable. The thyclotides are useful as reagents for antisense and antigene applications, and as probes in molecular diagnostics and microarrays.