MiniPEG-Modified Gamma-PNA Oligomers for Solubility and Hybridization

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Solution Overview

Problem

Peptide nucleic acids (PNAs) face challenges due to poor water solubility, propensity to aggregate, and non-specific binding, which hinders their handling and processing, and high synthesis costs limit their use in diagnostic assays and gene therapy.

Innovation Solution

A hydrophilic PNA moiety with a polyethyleneglycol (PEG) sidechain at the γ-carbon of the backbone, known as the (R)-miniPEG PNA unit, is designed to enhance hybridization properties, solubility, and biocompatibility, while maintaining sequence specificity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If PNA backbone is used, then hybridization affinity and sequence selectivity are improved, but water solubility deteriorates and aggregation propensity increases

Engineering Contradiction:

Improvehybridization affinityVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces a charged amino acid residue (lysine or arginine) at a specific local position (N-terminus or internal position) of the PNA oligomer to provide localized charge that improves water solubility without altering the entire backbone structure, thus maintaining hybridization affinity while addressing solubility issues

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates a composite PNA structure by combining the original PNA backbone with charged amino acid residues, forming a hybrid molecule that exhibits both the high hybridization affinity of PNA and the improved water solubility of charged residues

Inventive Principle:

Principle #40Composite materials

2Object-affected harmful factors

If charged amino acid residues are incorporated to improve water solubility, then solubility is improved, but binding affinity and sequence specificity deteriorate

Engineering Contradiction:

Improvewater solubilityVSAvoidbinding affinity

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The charged amino acid residues are placed at specific local positions (N-terminus or internal positions) rather than throughout the entire oligomer, providing solubility enhancement at minimal impact on the hybridization interface, thus preserving binding affinity and sequence specificity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent incorporates charged amino acid residues in limited quantities (one or more residues in a 5-25 mer oligomer) rather than excessive amounts, providing sufficient solubility improvement while minimizing interference with binding affinity and sequence specificity

Inventive Principle:

Principle #16Partial or excessive action

3Adaptability or versatility

If PNA is used for diagnostic assays and gene therapy, then therapeutic potential is improved, but synthesis cost increases

Engineering Contradiction:

Improvetherapeutic potentialVSAvoidsynthesis cost

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent modifies the PNA structure by incorporating standard charged amino acid residues (lysine or arginine) that can be synthesized using conventional chemical synthesis methods, thereby maintaining therapeutic potential while reducing synthesis complexity and cost compared to more complex PNA modifications

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11279736B2Conformationally-preorganized, MiniPEG-containing gamma-peptide nucleic acids

Publication Date: 2022.03.22 CARNEGIE MELLON UNIV

AI summary

The present invention relates to γ-PNA monomers according to Formula I where substituent groups R1, R2, R3, R4, R5, R6, B and P are defined as set forth in the specification. The invention also provides methodology for synthesizing compounds according to Formula I and methodology for synthesizing PNA oligomers that incorporate one or more Formula I monomers.