TPST-Expressing Therapeutics for HIV Neutralization
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Solution Overview
Problem
Current therapeutic compositions for HIV infection, such as antibody-like immunoadhesins and broadly neutralizing antibodies, have limitations including lower affinity for HIV Env, compromised potency, and resistance issues with a large fraction of HIV-1 isolates.
Innovation Solution
Development of therapeutic compositions containing a polynucleotide sequence expressing tyrosylprotein sulfotransferase (TPST) and a binding molecule that, upon tyrosine-sulfation by TPST, can bind to the gp120 protein of primate lentiviruses or neutralize infection, with a molar ratio of TPST to binding molecule greater than 1:10.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If broadly neutralizing antibodies (bNAbs) are used as therapeutics, then protection against HIV infection is provided, but a large fraction of HIV-1 isolates remain partially or wholly resistant
Solution Approach 1:
The patent employs a composite therapeutic approach by combining two distinct molecules: an immunoadhesin (CD4-Ig) that binds to the CD4-binding site on gp120, and a CCR5-mimetic peptide that binds to the coreceptor-binding site on gp120. This dual-component composite strategy allows simultaneous engagement of two different functional sites on the viral envelope protein, thereby achieving broad neutralization across diverse HIV-1 isolates including those resistant to single-antibody therapies.
2Reliability
If immunoadhesins (e.g., CD4-Ig) are used as therapeutics, then most HIV isolates are neutralized, but affinity for Env is lower than bNAbs and potency is compromised by parallel ability to promote infection
Solution Approach 1:
The patent merges the functional capabilities of two separate therapeutic agents into a single composite molecule or coordinated pair: the immunoadhesin component provides robust neutralization by blocking the CD4-binding site, while the CCR5-mimetic peptide component enhances binding affinity by mimicking the natural coreceptor CCR5 and engaging the coreceptor-binding site on gp120. This merging strategy overcomes the individual limitations of each agent.
Solution Approach 2:
The therapeutic composition is structured as a composite system where the immunoadhesin and CCR5-mimetic peptide work synergistically. The immunoadhesin provides the structural framework for neutralization, while the CCR5-mimetic peptide enhances binding strength and specificity, creating a composite therapeutic with superior overall performance compared to either component alone.
3Reliability
If CCR5 mimetics are developed as therapeutics, then HIV infection protection is attempted, but satisfactory therapeutic results are not achieved
Solution Approach 1:
The CCR5-mimetic peptide serves as an intermediary molecule that bridges the gap between the immunoadhesin and the viral gp120 protein. By mimicking the natural CCR5 coreceptor, it mediates high-affinity binding to the coreceptor-binding site on gp120, thereby enhancing the overall therapeutic efficacy of the composition. The peptide acts as a molecular mediator that translates the binding event into potent neutralization.
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 therapeutic compositions achieve potent and broad protection against HIV infection by optimizing the sulfation of the binding molecule, leading to enhanced binding affinity and neutralization capabilities, even against resistant isolates.
Implementation Method 1
a first polynucleotide sequence expressing a tyrosylprotein sulfotransferase (TPST), and a second polynucleotide sequence expressing a binding molecule that, upon tyrosine-sulfation by the TPST, is capable of binding to a gp120 protein
Data Source
AI summary
The present invention provides methods and compositions for optimally co-expressing in a primate subject a tyrosylprotein sulfotransferase (TPST) and a lentiviral gp120-binding molecule to provide potent and long term protection against lentiviral infections.