Targeted nCoVshRNA–ACE2 Synthesis for Variant-Resistant Delivery
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Solution Overview
Problem
Current siRNA drugs for COVID-19 are often designed for a single strain and can be off-target due to virus mutation, and non-targeted delivery vectors deliver siRNA to cells that are not susceptible to infection, necessitating a targeted delivery vector that can specifically deliver siRNA to virus-infected cells and resist variant strains.
Innovation Solution
A targeted drug nCoVshRNA·2ACE2 is synthesized by ligating an ACE2 polypeptide to double-strand ends of a double-stranded shRNA, using a bivalent ACE2 to bind to the virus RBD, neutralize it, and deliver the shRNA to target cells, forming a complex that enters the cells to interfere with viral replication.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If single-strain siRNA is used, then the drug can be simple to manufacture, but it becomes off-target and ineffective due to virus mutation
Solution Approach 1:
The patent designs siRNA sequences that target conserved regions of the coronavirus genome that remain unchanged across different strains and mutations. By targeting these universal conserved sequences, a single siRNA drug can effectively neutralize multiple viral variants without requiring strain-specific customization, thus achieving both manufacturing simplicity and broad-spectrum effectiveness.
2Device complexity
If non-targeted delivery vector is used, then the delivery system is simple, but the siRNA is delivered to cells that are not susceptible to coronavirus infection
Solution Approach 1:
The patent uses the ACE2 protein as a mediator between the siRNA drug and the target cells. The ACE2 polypeptide is conjugated to the siRNA to form a targeted delivery complex that specifically binds to ACE2 receptors on coronavirus-infected cells. This intermediary approach ensures that the siRNA is delivered precisely to susceptible target cells while avoiding non-targeted delivery to non-susceptible cells, achieving high delivery specificity without excessive system complexity.
3Ease of manufacture
If single-stranded siRNA is used, then the drug preparation is simple, but the silencing efficiency is low compared to double-stranded RNA
Solution Approach 1:
The patent employs double-stranded RNA (dsRNA) or short hairpin RNA (shRNA) structures instead of single-stranded siRNA. These composite RNA structures consist of sense and antisense strands that form stable double-helical configurations. The dsRNA/shRNA structures are processed by cellular Dicer enzymes to generate functional siRNA, providing significantly enhanced gene silencing efficiency compared to single-stranded approaches, while still maintaining relatively simple preparation protocols through in vitro transcription or chemical synthesis methods.
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 nCoVshRNA·2ACE2 effectively targets and interferes with variant strains of COVID-19 by specifically delivering shRNA to infected cells, neutralizing the virus, and stimulating the host to produce ACE2-Ab, providing broad-spectrum antiviral protection.
Implementation Method 1
The coronavirus binds to the ACE2 of a target cell through its S 1-RBD, and undergoes membrane fusion and endocytosis, such that the coronavirus enters the target cell through an ACE2 channel. This shows that coronavirus RBD and target cell ACE2 have a ligand-receptor relationship.
Data Source
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AI summary
A synthesis method of a targeted drug nCoVshRNA 2ACE2 of a COVID-19 virus,which includes the following steps: designing a consensus RNAi sequence siRNA of the COVID-19 virus and a variant strain thereof; synthesizing two complementary siRNAs into a small hairpin-shaped shRNA with a loop, and synthesizing ACE2 or a cell penetrating peptide ACE2 with a receptor-binding domain (RBD) as a ligand; and ligating the ACE2 to a sense strand and an antisense strand of the shRNA separately to synthesize the nCoVshRNA 2ACE2 including a shRNA region and an ACE2 region. The bivalent ACE2 functions to neutralize the RBD and deliver the shRNA in a targeted manner; an "shRNA-ACE2-RBD-virus" complex bridged by the ACE2 allows the shRNA to enter target cells with virus infection, thereby avoiding a side effect of non-specific delivery of the shRNA to uninfected cells, as well as resisting the variant strain and neutralizing the virus with the ACE.