HDAC6 Ubiquitin-Binding Inhibitor Blocks Viral Replication

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Solution Overview

Problem

Current treatments for virus infections, such as those caused by influenza A virus and SARS-CoV-2, face challenges in effectively targeting the ubiquitin-proteasome system and the interaction between unanchored ubiquitin chains and HDAC6, which are crucial for viral infectivity and cellular processes like inflammation.

Innovation Solution

A recombinant binding protein specifically binds to the ubiquitin-engaging zinc finger domain of HDAC6, blocking its interaction with ubiquitin chains, thereby inhibiting viral infection and inflammation. This protein, called F10, is designed to compete with endogenous binders and has a high affinity for the HDAC6 domain, disrupting the ubiquitin-HDAC6 interaction.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If small molecule inhibitors targeting HDAC6 deacetylase activity are used, then cancer models show efficacy, but viral infection treatment effectiveness is insufficient

Engineering Contradiction:

Improveefficacy in cancer modelsVSAvoideffectiveness against viral infections

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The invention develops distinct inhibitors with selective targeting: HDAC6 deacetylase activity inhibitors for cancer treatment, and HDAC6 ubiquitin-binding domain inhibitors for antiviral therapy. This local differentiation of inhibitory targets allows each compound class to optimize its therapeutic effect for its intended application without cross-interference.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The HDAC6 protein is functionally segmented into two distinct targets: the deacetylase catalytic domain and the ubiquitin-binding domain. The invention creates separate inhibitor molecules for each segment, enabling independent optimization of therapeutic properties for cancer versus antiviral applications.

Inventive Principle:

Principle #1Segmentation

2Stability of the object's composition

If the HDAC6 zinc finger domain structure is maintained, then ubiquitin binding function is preserved, but viral infectivity is enabled

Engineering Contradiction:

Improvezinc finger domain structureVSAvoidviral infectivity

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The invention introduces small molecule inhibitors as intermediaries that bind to the HDAC6 ubiquitin-binding domain, thereby blocking the interaction between HDAC6 and ubiquitin chains. This intermediary binding prevents viral exploitation of the HDAC6-ubiquitin interaction while preserving the structural integrity of the zinc finger domain.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention selectively extracts or removes the ubiquitin-binding function from HDAC6 through specific inhibition, while leaving the deacetylase catalytic function intact. This selective extraction of function allows differential therapeutic applications.

Inventive Principle:

Principle #2Taking out (Extraction)

3Object-affected harmful factors

If proteasome inhibitors are used to block viral entry, then influenza A virus infection is inhibited, but cellular metabolic processes are disrupted

Engineering Contradiction:

Improveviral entryVSAvoidcellular metabolism disruption

Core Design Contradiction:

Object-affected harmful factorsVSObject-generated harmful factors

Solution Approach 1:

Instead of inhibiting the proteasome system broadly (which affects both viral entry and cellular metabolism), the invention inverts the approach by specifically targeting the HDAC6 ubiquitin-binding domain. This selective targeting blocks viral exploitation of ubiquitin pathways without disrupting the overall proteasome-mediated cellular metabolic processes.

Inventive Principle:

Principle #13The other way round (Inversion)

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 recombinant binding protein effectively blocks the ubiquitin-HDAC6 interaction, reducing viral replication and infectivity, as demonstrated by its ability to inhibit influenza A virus and Zika virus infections, showcasing its therapeutic potential in treating viral infections.

Implementation Method 1

A recombinant binding protein specifically binds to the ubiquitin-engaging zinc finger domain of HDAC6, blocking its interaction with ubiquitin chains

Methodology Applied

Scientific EffectProtein-protein interaction:

Implementation Method 2

This protein, called F10, is designed to compete with endogenous binders and has a high affinity for the HDAC6 domain, disrupting the ubiquitin-HDAC6 interaction

Methodology Applied

Scientific EffectCompetitive inhibition:

Data Source

PatentUS20240018265A1HDAC6 binding proteins and their Anti-viral use

Publication Date: 2024.01.18 NOVARTIS FORSCHUNGSSTIFTUNG ZWEIGNIEDERLASSUNG FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL RESEARCH

AI summary

The present application provides a recombinant binding protein that specifically binds to HDAC6 and blocks the ubiquitin-engaging zinc finger domain of HDAC6.