Colorectal Cancer Virus with Mutated HN Protein Binding
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current oncolytic viruses, such as the Newcastle disease virus (NDV), lack cancer cell-specific infectivity, leading to reduced efficacy due to non-specific infection of both cancer and normal cells, and high concentrations are required to overcome dilution effects in the bloodstream, causing immune responses and secondary side effects.
Innovation Solution
A recombinant NDV vector is developed with mutations in the HN protein's globular head domain to enhance colorectal cancer cell binding, combined with a transgene cassette for introducing genes that induce cancer apoptosis, creating a colorectal cancer-targeted oncolytic virus.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If a high concentration of oncolytic virus is used to overcome dilution effects in the bloodstream, then the virus can effectively infect cancer cells, but it causes immune responses and secondary side effects
Solution Approach 1:
The HN protein of the Newcastle disease virus is modified to specifically recognize and bind to sialic acid residues on colorectal cancer cell surfaces. This local modification of viral binding properties enables the virus to selectively infect cancer cells while avoiding normal cells, thereby maintaining efficacy at lower concentrations and reducing immune responses and side effects
Solution Approach 2:
The amino acid sequence of the HN protein is altered through site-directed mutagenesis to change its binding specificity. By modifying specific amino acid residues in the globular head domain, the virus gains enhanced affinity for colorectal cancer cell surface receptors, allowing effective infection at reduced viral concentrations that minimize harmful immune responses
2Adaptability or versatility
If the oncolytic virus is injected intravenously for systemic delivery, then it can reach cancer cells throughout the body, but the concentration is reduced by the dilution effect primarily caused by blood
Solution Approach 1:
The virus is engineered with enhanced local binding properties through HN protein modification, allowing it to specifically recognize and bind to colorectal cancer cells. This increased binding affinity compensates for the dilution effect during intravenous circulation, enabling effective cancer cell infection throughout the body at lower overall viral doses
3Adaptability or versatility
If the oncolytic virus infects both cancer and normal cells, then it can broadly target potential cancer cells, but it cannot specifically kill only the cancer cells
Solution Approach 1:
The HN protein is modified to specifically recognize sialic acid residues with particular structural characteristics that are predominantly expressed on colorectal cancer cell surfaces. This localized modification of viral recognition properties enables selective infection of cancer cells while sparing normal cells, achieving both specificity and targeted efficacy
Solution Approach 2:
The modified HN protein acts as a selective intermediary that mediates between the virus and host cells. By altering the protein's binding interface, the virus gains selective access to colorectal cancer cells through specific molecular interactions, preventing infection of normal cells while maintaining ability to infect and kill cancer cells
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 modified virus demonstrates increased specificity and efficacy in targeting colorectal cancer cells, reducing side effects and improving treatment outcomes by enhancing cancer cell killing and immune response induction.
Implementation Method 1
HN protein binds to a sialic acid (glycoprotein) on the cell surface
Implementation Method 2
HN protein binds to a sialic acid (glycoprotein) on the cell surface, and then cleaves the bound sialic acid by neuramidase
Implementation Method 3
causes fusion of the cell membrane of host cells and the envelope of NDV virus by F protein
Data Source
AI summary
Provided is an M2-LVP-K1 virus including a colorectal cancer cell-specific mutant sialic acid binding domain and a composition for treating colorectal cancer including the same. The mutant sialic acid binding domain is constructed using directed evolution technology, and is a recombinant Newcastle disease virus constructed by substituting a normal sialic acid binding domain for a HN protein, a cell-binding receptor, to improve the specific infectivity to HCT116 cells. It was identified that M2-LVP-K1 recombinant Newcastle disease virus with improved colorectal cancer cell-specific infectivity has improved HCT116 cell death effect compared to the conventional normal recombinant Newcastle disease virus, and produces an excellent effect in inhibiting cancer tissue growth through in vivo experiments. The mutant recombinant Newcastle disease virus presented in this study relates to a therapeutic viral agent capable of inducing clinical symptom reduction, partial remission, or complete remission through colorectal cancer cell death or colorectal cancer tissue shrinkage.