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, retaining membrane fusion ability but losing interaction with LDL membrane receptors, allowing targeted delivery to tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If VSV-G protein is used for pseudotyping lentiviruses, then broad tropism is achieved due to ubiquitous LDL-R distribution, but specific targeting of tumor cells is lost
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions at defined positions (8, 47, 209, and/or 354) of the VSV-G protein sequence. These localized modifications alter the protein's interaction properties with LDL-R receptors, enabling the virus to lose affinity for ubiquitous LDL-R while retaining or gaining affinity for tumor-specific receptors, thus achieving specific targeting without sacrificing overall adaptability
Solution Approach 2:
The patent employs parameter changes by systematically modifying the amino acid sequence parameters of VSV-G at specific positions. These parameter changes (substitutions at positions 8, 47, 209, and/or 354) fundamentally alter the protein's binding characteristics, transforming it from a broad-tropism vector to a tumor-specific targeting vehicle while maintaining membrane fusion capability
2Ease of manufacture
If amino acid substitutions are introduced at positions 8, 47, 209, and/or 354 of VSV-G, then interaction with LDL-R is lost enabling tumor targeting, but membrane fusion ability must be retained
Solution Approach 1:
The patent applies segmentation by separating the functional domains of VSV-G protein. The amino acid substitutions at positions 8, 47, 209, and/or 354 specifically modify the receptor-binding region to eliminate LDL-R interaction, while the membrane fusion domain remains intact and functional. This segmentation allows independent optimization of targeting and fusion functions
Solution Approach 2:
The patent uses the mutated VSV-G protein as an intermediary that mediates between tumor cell recognition and membrane fusion events. The specific amino acid substitutions create a modified protein that first binds to tumor-specific receptors (not LDL-R), then facilitates membrane fusion through its preserved fusion machinery, effectively bridging targeting and entry functions
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 selective targeting of tumor cells while maintaining membrane fusion capability, enhancing the therapeutic efficacy of oncolytic viruses.
Implementation Method 1
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. Fusion is catalyzed by a low-pH-induced large structural transition from a pre-toward a post-fusion conformation
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.