VHH Polypeptides Targeting Viral Receptors for Entry Inhibition
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Solution Overview
Problem
Current antiviral therapies face challenges in effectively inhibiting the entry of viruses such as HIV, HCV, adenoviruses, hantavirus, and herpesvirus into human cells, as existing treatments often have limitations in specificity, efficacy, and solubility, and may not adequately target key cellular receptors like hCD4, hCXCR4, and hTLR4.
Innovation Solution
Development of polypeptides comprising VHHs that specifically bind to human cellular receptors, including hCD4, hCXCR4, and hTLR4, with defined amino acid sequences that inhibit viral entry, and nucleic acids encoding these sequences, which can be used to create pharmaceutical compositions for prophylactic, therapeutic, and diagnostic purposes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antiviral therapies are used, then viral entry inhibition is attempted, but specificity and efficacy are insufficient
Solution Approach 1:
The patent segments the antibody structure into separate VHH domains, each targeting specific viral receptors independently. This segmentation allows for improved specificity against different viral entry mechanisms while maintaining manageable structural complexity through modular design of single-domain antibody fragments
Solution Approach 2:
The patent applies local quality by engineering VHHs with specific affinity characteristics for different viral receptors (CD4, CXCR4, CCR5, integrins, claudins). Each VHH domain is optimized with specific binding properties tailored to its target receptor, enhancing overall efficacy without requiring uniform complexity across the entire therapeutic molecule
2Reliability
If polypeptides with high binding affinity are developed, then viral entry prevention is improved, but manufacturing complexity increases
Solution Approach 1:
The patent extracts only the essential antigen-binding variable domain (VHH) from the complete antibody structure. This extraction eliminates the need to manufacture and purify complex full-length antibodies while retaining the critical high-affinity binding function, significantly simplifying manufacturing processes
Solution Approach 2:
The VHH domains are designed as smaller, simpler molecular entities that can be produced more easily and at lower cost than conventional antibodies. Although individual VHHs have shorter half-lives, their ease of manufacture and ability to be administered in combination or as part of multimeric constructs provides a practical manufacturing advantage
3Reliability
If multiple VHHs are combined in polypeptides, then neutralization efficacy is enhanced, but device complexity increases
Solution Approach 1:
The patent merges multiple VHH domains into single polypeptide constructs to achieve synergistic neutralization of viral entry. By combining VHHs targeting different receptors (e.g., CD4 plus CXCR4, or multiple integrin-targeting VHHs), the polypeptides achieve enhanced efficacy through cooperative binding while maintaining a relatively simple modular structure
Solution Approach 2:
The patent creates multivalent VHH polypeptides that can simultaneously target multiple viral receptors and potentially multiple viruses. This multi-functionality allows a single therapeutic agent to neutralize diverse viral entry mechanisms, enhancing overall efficacy without requiring separate treatments for each viral target
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 polypeptides effectively prevent viral entry by binding to specific receptors with high affinity, offering a promising approach for treating and preventing viral infections by modulating viral attachment and fusion processes.
Implementation Method 1
VHHs that specifically bind CD4 and that inhibit viral entry
Implementation Method 2
binding to specific receptors with high affinity
Implementation Method 3
inhibit viral entry, offering a promising approach for treating and preventing viral infections by modulating viral attachment and fusion processes
Data Source
Figure 1
Figure 2
Figure 3A.1
AI summary
The present invention relates to amino acid sequences that are directed against (as defined herein) human cellular receptors for viruses and/or bacteria such as e.g. Nanobodies specifically recognizing hCD4, hCXCR4, hCCR5. hTLR4, human alphaV integrin, human beta3 integrin, human betal integrin, human alpha2 integrin, hCD81, hSR-Bl, hClaudin-1, hClaudin-6 and hClaudin-9, as well as to compounds or constructs, and in particular proteins and polypeptides, that comprise or essentially consist of one or more such amino acid sequences. Said amino acid sequences may be used to prevent human cell entry of HIV, HCV, adenoviruses, hantavirus, herpesvirus, echo-virus 1 and others.