Mutated VSV-G Glycoprotein for Tumor-Selective Viral Targeting
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Solution Overview
Problem
VSV-G pseudotyped lentiviruses exhibit broad tropism due to the ubiquitous distribution of LDL-R receptors, limiting their therapeutic use, particularly in oncotherapy where specific targeting of tumor cells is desired.
Innovation Solution
A mutated VSV-G protein with specific amino acid substitutions at positions 8, 47, 209, and/or 354, which retains membrane fusion ability but loses interaction with LDL membrane receptors, allowing targeted delivery to tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If VSV-G pseudotyped lentiviruses are used, then broad tropism is achieved, but specific targeting of tumor cells is lost
Solution Approach 1:
The patent applies local quality by introducing specific amino acid mutations at defined positions (8, 47, 209, 354) in the VSV-G protein to selectively alter receptor binding properties. These localized changes in specific regions of the protein enable the virus to lose interaction with LDL-R receptors while maintaining membrane fusion capability, thereby achieving tumor cell specificity without compromising overall viral function.
Solution Approach 2:
The patent employs parameter changes by modifying the amino acid sequence parameters of the VSV-G protein at specific positions. By changing the chemical properties and binding characteristics of these amino acid residues, the virus transitions from broad tropism to tumor-specific targeting. The mutations alter the protein's interaction parameters with cellular receptors while preserving fusogenic activity.
2Manufacturing precision
If mutations are introduced in VSV-G protein, then specific targeting is achieved, but membrane fusion ability may be compromised
Solution Approach 1:
The patent applies segmentation by separating the functional domains of the VSV-G protein into distinct regions with specific roles. The mutations are introduced in specific segments (positions 8, 47, 209, 354) that are responsible for receptor binding, while leaving other segments intact that maintain membrane fusion capability. This functional segmentation allows independent optimization of targeting and fusion properties.
Solution Approach 2:
The patent uses an intermediary approach by identifying and mutating specific amino acid positions that act as intermediaries between the virus and host cell receptors. These positions (8, 47, 209, 354) serve as critical interaction points with LDL-R receptors. By modifying these intermediary residues, the virus achieves specific targeting while preserving the downstream membrane fusion function through intact fusion domains.
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 mutated VSV-G protein enables specific targeting of tumor cells while maintaining membrane fusion capability, enhancing the therapeutic efficacy of oncolytic viruses.
Implementation Method 1
G plays a critical role during the initial steps of virus infection. First, it is responsible for virus attachment to specific receptors. After binding, virions enter the cell by a clathrin-mediated endocytic pathway.
Implementation Method 2
In the acidic environment of the endocytic vesicle, G triggers the fusion between the viral and endosomal membranes, which releases the genome in the cytosol for the subsequent steps of infection.
Implementation Method 3
Fusion is catalyzed by a low-pH-induced large structural transition from a pre-toward a post-fusion conformation which are both trimeric
Data Source
AI summary
The invention relates to an isolated non-naturally occurring protein comprising the amino acid sequence as set forth in SEQ ID NO: 1, and wherein the amino acid in position 8, 47, 209 and/or 354 is substituted by any amino acid different from the amino acid indicated at that position in said sequence SEQ ID NO: 1.