Conformation-Selective NTCP Binders for Liver-Targeted Antiviral Delivery
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Solution Overview
Problem
Current treatments for chronic hepatitis B and D infections and liver diseases lack highly specific and selective binders for the human Na+-taurocholate co-transporting polypeptide (NTCP) that can effectively inhibit bile salt transport and viral entry, while also providing targeted drug delivery to hepatocytes.
Innovation Solution
Development of immunoglobulin single variable domain (ISVD) binders that stabilize specific conformational states of NTCP, either the inward-facing or open-pore state, to allosterically inhibit bile salt transport and block hepatitis B and D virus entry, using ISVDs such as Nb87 and Nb91, which are conformation-selective and do not sterically hinder substrate binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional binders are used to inhibit NTCP transport activity, then viral entry is blocked, but substrate binding is sterically hindered
Solution Approach 1:
The ISVD binders are designed to bind specifically to particular conformational states of NTCP (inward-facing or open-pore states) rather than blocking the substrate binding site directly. This localized binding approach allows the binders to stabilize specific conformations that are less competent for substrate transport while preserving normal substrate binding capability.
Solution Approach 2:
The invention exploits conformational parameter changes in NTCP by stabilizing specific conformational states (inward-facing or open-pore) through ISVD binding. This conformational stabilization alters the transport cycle dynamics, creating a state that is less competent for substrate transport while maintaining substrate binding ability, thus resolving the contradiction between viral entry inhibition and substrate binding preservation.
2Adaptability or versatility
If highly specific NTCP binders are developed for targeted delivery, then liver-specific delivery is achieved, but complexity of binder design increases
Solution Approach 1:
The ISVD binders serve multiple functions simultaneously: they act as conformation-selective inhibitors of NTCP transport, serve as antiviral agents by blocking viral entry, and function as targeted delivery vehicles to hepatocytes. This multi-functionality is achieved through the inherent conformation-selective binding properties of ISVDs to NTCP, eliminating the need for separate targeting mechanisms and reducing overall system complexity.
3Reliability
If conformation-selective binders are used to stabilize NTCP states, then allosteric inhibition of transport is achieved, but difficulty in identifying effective conformations increases
Solution Approach 1:
The invention employs a systematic approach where ISVD binders are screened and characterized based on their ability to stabilize specific NTCP conformations. The conformational states are identified and characterized through structural and functional assays, providing feedback on which conformations are most effective for allosteric inhibition. This feedback-driven approach enables the identification of optimal conformational targets for therapeutic intervention.
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 ISVD binders effectively inhibit NTCP transport activity and viral entry, providing novel antiviral therapy and liver-specific targeted drug delivery without interfering with substrate binding, and enable structural analysis of NTCP conformations.
Implementation Method 1
ISVD binders that stabilize specific conformational states of NTCP, either the inward-facing or open-pore state, to allosterically inhibit bile salt transport and block hepatitis B and D virus entry
Data Source
AI summary
The disclosure relates to binding agents and compositions specifically binding the human Na+-taurocholate co-transporting polypeptide (NTCP/SLC10A1), thereby stabilizing a NTCP conformational state which allosterically inhibits its bile salt transport function. More specifically, the disclosure discloses Nanobodies that lock an inward-facing or open-pore NTCP conformational state, thereby useful as novel hepatitis virus B (HBV) and/or hepatitis virus D (HDV) antiviral, for treatment of liver disease, or as vehicle for targeted-delivery to the liver. Finally, the disclosure relates to a screening assay wherein said Nanobodies are used as a tool to identify NTCP conformation-selective compounds with therapeutic potential.