NTCP-Targeting Conjugate Compounds for HBV Entry Inhibition
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Solution Overview
Problem
Current treatments for chronic hepatitis B virus (HBV) and Hepatitis Delta Virus (HDV) infections are inadequate, with limited therapeutic options and high rates of chronic infection, and existing therapies primarily target viral replication rather than virus entry, leading to suboptimal patient responses.
Innovation Solution
Development of conjugate compounds comprising a hydrophobic modified preS-derived peptide of hepatitis B virus and a NTCP substrate moiety, covalently attached, which target the sodium taurocholate co-transporting polypeptide (NTCP) receptor to inhibit virus entry.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapies target viral replication, then viral replication is inhibited, but virus entry is not blocked leading to suboptimal patient responses
Solution Approach 1:
The invention segments the antiviral strategy into two distinct components: (1) blocking virus entry at the cellular level using NTCP-targeting compounds, and (2) inhibiting viral replication intracellularly using existing antivirals. This segmentation allows each component to address a specific stage of the viral lifecycle, thereby improving overall treatment effectiveness and reducing the risk of viral escape mutations.
Solution Approach 2:
The NTCP-targeting compounds developed in this invention have dual functionality: they serve as both entry inhibitors blocking HBV and HDV at the cell surface, and can be combined with various existing antivirals targeting different replication steps. This multi-functionality creates a versatile therapeutic platform applicable to multiple virus types and resistance scenarios.
2Productivity
If only viral replication is targeted, then replication is reduced, but chronic infection persists due to incomplete elimination
Solution Approach 1:
The invention applies preliminary action by blocking virus entry before the virus can establish intracellular replication. By preventing viral particles from entering hepatocytes through NTCP receptor blockade, the virus is eliminated at the earliest possible stage, preventing infection establishment and thereby improving cure rates alongside productivity.
3Reliability
If novel entry inhibitors are developed, then virus entry is blocked, but therapeutic complexity increases
Solution Approach 1:
The NTCP receptor serves as an intermediary target that natural bile acids already interact with. By designing entry inhibitors based on modified bile acid structures that mimic natural substrates, the invention leverages an existing physiological pathway, simplifying the therapeutic approach compared to targeting entirely novel viral proteins or cellular receptors.
Solution Approach 2:
The invention employs parameter changes by modifying the chemical structure of natural bile acids (the substrates of NTCP) to create high-affinity inhibitors. By altering parameters such as hydroxyl group positions, side chain lengths, and stereochemistry of bile acid molecules, potent entry inhibitors are generated that maintain simplicity through structural resemblance to endogenous compounds.
Data Source
AI summary
The present invention relates to conjugate compounds which comprise a peptide moiety (a) which is preferably a hydrophobic modified preS-derived peptide of hepatitis B virus or a respective cyclic peptide, and a NTCP substrate moiety (b), which is preferably a bile acid. The present invention further relates to pharmaceutical compositions comprising at least one conjugate compound. The present invention further relates to medical uses of said conjugate compounds and the pharmaceutical compositions, such as in the diagnosis, prevention and/or treatment of a liver disease or condition, and/or in the inhibition of HBV and/or HDV infection. The present invention further relates to methods of diagnosis, prevention and/or treatment of a said diseases and/or infections.