Nucleic Acid Binding Polymers for TLR Inhibition
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Solution Overview
Problem
Current therapies targeting individual Toll-like receptors (TLRs) are limited by redundancy and interconnectedness of the TLR signaling pathway, necessitating the development of agents that can inhibit multiple TLRs simultaneously to effectively control inflammatory and autoimmune responses.
Innovation Solution
Cyclodextrin-containing polymers and polybrene, with high binding affinity for nucleic acids, are used to inhibit the activation of TLR3 and TLR9, independent of nucleotide sequence, chemistry, or structure, thereby preventing or inhibiting the progression of nucleic acid-induced thrombotic disorders and inflammatory responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If individual TLR inhibitors are used, then specific TLR activation is blocked, but the redundancy and interconnectedness of TLR signaling limits therapeutic efficacy
Solution Approach 1:
The patent applies universality by developing a single nucleic acid binding agent that can simultaneously inhibit multiple TLRs (TLR3, TLR7, TLR9) through a common mechanism of binding to nucleic acid ligands. This multi-functional approach overcomes the limitation of individual TLR inhibitors and addresses the redundancy in TLR signaling pathways, thereby improving therapeutic efficacy against diverse inflammatory and autoimmune conditions.
2Reliability
If nucleic acid binding agents are used to inhibit multiple TLRs, then therapeutic efficacy is improved, but the complexity of identifying and developing such agents increases
Solution Approach 1:
The patent employs an intermediary approach by using nucleic acid binding agents as universal mediators that interact with multiple TLRs through a common binding mechanism. These agents serve as intermediaries between the diverse nucleic acid ligands of different TLRs and the intracellular signaling pathways, simplifying the development process by providing a single point of intervention rather than requiring separate inhibitors for each TLR.
3Object-affected harmful factors
If TLR activation is inhibited to treat inflammatory diseases, then inflammatory responses are controlled, but the ability to mount appropriate immune responses may be compromised
Solution Approach 1:
The patent applies the extraction principle by specifically removing or neutralizing only the pathological nucleic acid ligands that inappropriately activate TLRs in inflammatory and autoimmune diseases. The nucleic acid binding agents selectively bind to and sequester these harmful nucleic acids (such as self-DNA or viral nucleic acids) without broadly suppressing the immune system's ability to respond to genuine threats, thus differentiating between harmful and beneficial TLR activation.
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
These polymers effectively reduce the production of inflammatory cytokines TNF-α and IL-6, alleviate acute liver inflammation, and demonstrate significant protection against TLR-mediated mortality in animal models, showcasing their potential in treating inflammatory and autoimmune diseases.
Implementation Method 1
Cyclodextrin-containing polymers and polybrene, with high binding affinity for nucleic acids, are used to inhibit the activation of TLR3 and TLR9
Data Source
Figure 1A
Figure 1B
Figure 2A~2B
AI summary
The present invention relates, in general, to pattern-recognition receptors (PRRs), including toll-like receptors (TLRs), and, in particular, to a method of inhibiting nucleic acid-induced activation of, for example, endosomal TLRs using an agent that binds to the nucleic acid ("nucleic acid binding agent"), preferably, in a manner that is independent of the nucleotide sequence, the chemistry (e.g., DNA or RNA, with or without base or sugar modifications) and/or the structure (e.g., double-stranded or single-stranded, complexed or uncomplexed with, for example protein) of the nucleic acid(s) responsible for inducing TLR activation. The invention also relates to methods of identifying nucleic acid binding agents suitable for use in such methods.