Artificial Antibody shRNA-ACE2 Hybrid for Coronavirus Neutralization

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Solution Overview

Problem

Current antiviral therapies, including vaccines and siRNA drugs, are limited in their ability to effectively target and neutralize multiple coronavirus variants due to their specificity to single strains and poor delivery mechanisms, leading to off-target effects and reduced efficacy against mutating viruses.

Innovation Solution

Development of a broad-spectrum artificial antibody that combines a shRNA duplex with ACE2 polypeptides at both ends, mimicking the structure of immunoglobulins to bind to the viral RBD, facilitating targeted delivery and neutralization of multiple coronavirus variants while enhancing stability and permeability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If single-stranded siRNA is used for antiviral therapy, then the drug can be prepared and delivered, but the silencing efficiency is low and off-target effects occur

Engineering Contradiction:

Improvesilencing efficiencyVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the structural parameter of siRNA from single-stranded to double-stranded configuration, which fundamentally alters the RNA interference mechanism to achieve over 100 times higher silencing efficiency while reducing off-target effects through proper duplex formation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite structure by ligating ACE2 polypeptides at both ends of the shRNA duplex, forming a hybrid molecule that combines the antiviral binding capability of ACE2 with the gene silencing function of shRNA for targeted delivery

Inventive Principle:

Principle #40Composite materials

2Ease of manufacture

If siRNA drugs are designed using a single strain, then the drug development process is simplified, but the drug becomes ineffective against mutated coronavirus strains

Engineering Contradiction:

Improvedrug development processVSAvoidbroad-spectrum antiviral effect

Core Design Contradiction:

Ease of manufactureVSAdaptability or versatility

Solution Approach 1:

The patent designs the shRNA sequence to target highly conserved regions of the coronavirus genome that remain unchanged across different variants, making the single siRNA sequence universally effective against multiple strains including mutated versions

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Ease of operation

If non-targeted delivery vectors are used for siRNA, then the delivery process is simple, but the siRNA causes off-target effects and has reduced efficacy

Engineering Contradiction:

Improvedelivery processVSAvoidtargeted delivery efficiency

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent uses ACE2 polypeptides as intermediary binding molecules that specifically recognize and bind to the viral RBD, thereby mediating the targeted delivery of the shRNA duplex to infected cells expressing the coronavirus spike protein

Inventive Principle:

Principle #24Intermediary (Mediator)

4Device complexity

If single-stranded siRNA is used, then the molecular structure is simple, but the RNA interference efficiency is extremely low

Engineering Contradiction:

Improvemolecular structureVSAvoidRNA interference efficiency

Core Design Contradiction:

Device complexityVSPower

Solution Approach 1:

Inventive Principle:

Principle #35Parameter changes

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 artificial antibody effectively neutralizes viral RBD, prevents viral infection by targeting conserved genes, and stimulates the host to produce ACE2-Ab, demonstrating a broad-spectrum antiviral effect with improved stability and targeted delivery of shRNA, thereby inhibiting viral replication across variant strains.

Implementation Method 1

Small interfering RNA, or siRNA, can regulate gene expression in a manner of participating in RNA interference (RNAi), thus specifically degrading a complementary target messenger RNA (mRNA)

Methodology Applied

Scientific EffectRNA interference:

Implementation Method 2

The ACE2 and the RBD act as a ligand and a receptor, respectively, and the ACE2 can neutralize the RBD

Methodology Applied

Scientific EffectReceptor-ligand binding:

Data Source

PatentUS20230203137A1Preparation method of artificial antibody

Publication Date: 2023.06.29 HANGZHOU CHICHUANG BIOTECHNOLOGY CO LTD

AI summary

The present disclosure provides a preparation method of an artificial antibody. The preparation method includes the following steps: screening a target siRNA from a conserved gene or a microsatellite of a coronavirus, synthesizing a small hairpin RNA (shRNA) that has a loop by complementary sense and antisense strands of the siRNA, synthesizing an ACE2 capable of binding to a receptor-binding domain (RBD), and synthesizing the artificial antibody including an shRNA region and an ACE2 region by ligating the ACE2 to sense and antisense strands of the shRNA separately. The bivalent ACE2 is used for neutralization of the RBD and targeted delivery of the shRNA; the shRNA is ligated to the virus through the ACE2 and enters 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 ACE2.