Phosphorothioate-Conjugated Peptides for Intracellular Delivery
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Solution Overview
Problem
Targeting intracellular molecules for therapeutic purposes is challenging due to the need for biostable compositions that can penetrate the cell membrane and maintain stability in a physiological environment, which existing technologies have not effectively addressed.
Innovation Solution
Development of nucleic acid-peptide conjugates, specifically non-cell penetrating peptides conjugated with phosphorothioate nucleic acids at their C-terminus, which enhance intracellular delivery and biostability, allowing for effective targeting of intracellular molecules involved in disease pathology.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-cell penetrating peptides are used to target intracellular molecules, then specificity to intracellular targets is improved, but cellular penetration ability deteriorates
Solution Approach 1:
The patent merges a non-cell penetrating peptide (providing target specificity) with a phosphorothioate nucleic acid (providing cellular penetration capability) to create a conjugate that exhibits both high specificity for intracellular targets and efficient cellular delivery. The peptide and nucleic acid are covalently linked through a chemical connector, allowing the conjugate to function as an integrated therapeutic agent that overcomes the limitation of individual components.
2Ease of operation
If peptides are designed to penetrate cell membranes, then cellular delivery is improved, but biostability in physiological environment deteriorates
Solution Approach 1:
The patent creates a composite conjugate consisting of a peptide component, a phosphorothioate nucleic acid component, and a chemical connector. The phosphorothioate backbone provides enhanced biostability by resisting nucleases and proteases in physiological environments, while the peptide component maintains target binding specificity. This composite structure resolves the contradiction between cellular delivery and biostability.
3Productivity
If cell penetrating peptides are used, then intracellular delivery efficiency is improved, but loss of therapeutic agent through rapid clearance deteriorates
Solution Approach 1:
The phosphorothioate nucleic acid acts as an intermediary carrier that facilitates intracellular delivery of the therapeutic peptide while protecting it from rapid clearance. The nucleic acid component enables cellular uptake through endocytosis or other nucleic acid delivery pathways, and its stable phosphorothioate backbone protects the conjugate from degradation by cellular enzymes, thereby reducing loss of the therapeutic agent.
Data Source
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AI summary
Provided herein are, inter alia, nucleic acid-peptide conjugates including a non-cell penetrating protein attached at its C-terminus to a phosphorothioate nucleic acid. Attachment of the phosphorothioate nucleic acid to the non-cell penetrating protein conveys stability to and allows for efficient intracellular delivery of the non-cell penetrating peptide. The nucleic acid-peptide conjugates provided herein including embodiments thereof are useful, inter alia, for the treatment of cancer, inflammatory disease, pain, and viral infection.