RAP Inhibitor Targets HBV Hepatocyte Entry

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Solution Overview

Problem

Current therapies for hepatitis B virus (HBV) infection, such as pegylated interferons and nucleoside or nucleotide analogues, have low response rates and induce drug resistance, and there is a lack of understanding of host factors required for HBV entry into hepatocytes, limiting effective treatment options.

Innovation Solution

Administering therapeutically effective amounts of low density lipoprotein receptor (LDLR), low density lipoprotein receptor-related protein (LRP), receptor-associated protein (RAP), LDLR or LRP inhibitors, or Factor Xa (FXa) inhibitors to inhibit HBV infection by interacting with the HBV receptor complex on hepatocytes, potentially combined with pegylated interferon or nucleoside/nucleotide analogues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If pegylated interferons are administered to treat HBV infection, then antiviral efficacy is improved, but response rate remains low and serious side effects occur

Engineering Contradiction:

Improveantiviral efficacyVSAvoidresponse rate

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent introduces host factor proteins (LDLR, LRP, RAP, or FXa) as intermediary molecules that mediate HBV entry into hepatocytes. By targeting these host factors rather than the virus directly, the invention achieves antiviral efficacy through a different mechanism that avoids the limitations of interferon therapy, potentially improving response rates while reducing side effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If nucleoside or nucleotide analogues are administered to inhibit HBV DNA replication, then replication inhibition is improved, but HBsAg clearance fails and drug resistance is induced

Engineering Contradiction:

Improvereplication inhibitionVSAvoidHBsAg clearance

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies preliminary action by blocking HBV entry into hepatocytes at the very first step of the viral lifecycle. By preventing virus internalization through host factor inhibition, the virus never establishes infection or produces HBsAg, thereby achieving both replication inhibition and HBsAg clearance simultaneously without inducing drug resistance.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If current HBV therapies are used to treat infection, then some viral inhibition is achieved, but sustained virological response is not obtained due to persistent cccDNA

Engineering Contradiction:

Improveviral inhibitionVSAvoidpersistent infection

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent applies preliminary anti-action by preventing HBV entry into hepatocytes before the virus can establish persistent infection. By blocking the entry mechanism at the host factor level, the invention prevents both acute infection and the formation of persistent cccDNA reservoirs, thereby achieving sustained virological response.

Inventive Principle:

Principle #9Preliminary anti-action

4Reliability

If HBV envelope proteins are targeted to block viral attachment, then entry inhibition may be improved, but high-affinity receptor identification has failed

Engineering Contradiction:

Improveentry inhibitionVSAvoidreceptor identification

Core Design Contradiction:

ReliabilityVSLoss of information

Solution Approach 1:

Instead of trying to identify the HBV receptor by analyzing viral envelope proteins, the patent inverts the approach by identifying host cell surface proteins (LDLR, LRP, RAP, FXa) that HBV must interact with for entry. This host-centric approach successfully identified the high-affinity receptor complex, resolving the information loss about receptor identity.

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentUS10442868B2Treating hepatitis B virus infections by administering receptor associated protein (RAP)

Publication Date: 2019.10.15 RHODE ISLAND HOSPITAL

AI summary

The specification provides compositions and methods of reducing a risk of a HBV infection in a subject and of treating a subject infected with HBV.