V2R Antagonist Peptides for Selective Aquaretic Blockade

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Solution Overview

Problem

Current V2R antagonists, such as tolvaptan, suffer from hepatotoxicity, limited selectivity, and incomplete blockade of V2R-associated signaling pathways, leading to undesirable effects and restricted use in clinical settings.

Innovation Solution

Development of a family of peptides with 80% or more amino acid identity to SEQ ID NO. 1, featuring specific structural modifications, including an alanine residue at position 39, which exhibit high affinity and selectivity for V2R, inhibiting cAMP production and inducing an aquaretic effect without significant immunogenicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If tolvaptan is used as a V2R antagonist, then V2R blockade is achieved, but hepatotoxicity occurs

Engineering Contradiction:

ImproveV2R blockade efficacyVSAvoidhepatotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the chemical structure parameters by developing peptide-based V2R antagonists with specific amino acid sequences (e.g., SEQ ID NO: 1 and variants) instead of using tolvaptan's benzazepine structure. This structural parameter change eliminates hepatotoxicity while maintaining V2R blockade efficacy, as demonstrated by the peptides' ability to inhibit cAMP production and induce aquaretic effects without liver damage.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If tolvaptan is used as a V2R antagonist, then V2R blockade is achieved, but selectivity is limited

Engineering Contradiction:

ImproveV2R blockade efficacyVSAvoidreceptor selectivity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by designing peptides with specific amino acid residues at critical positions (e.g., alanine at position 39, and specific residues at positions 10, 13, 27, 48) that create localized interaction features with the V2R binding pocket. These localized structural features enhance selectivity for V2R over other vasopressin receptors (V1a, V1b, oxytocin) while maintaining overall blockade efficacy.

Inventive Principle:

Principle #3Local quality

3Reliability

If tolvaptan is used as a V2R antagonist, then partial V2R blockade is achieved, but signaling pathways remain incomplete blocked

Engineering Contradiction:

Improvetherapeutic effectVSAvoidundesirable effects

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies preliminary action by designing peptides that pre-organize their structure to optimally block multiple V2R signaling pathways simultaneously. The specific amino acid sequences are configured in advance to interact with key residues in the V2R binding pocket, ensuring complete blockade of Gs-protein coupled cAMP production and other downstream pathways before pathological processes can occur, thereby eliminating undesirable effects.

Inventive Principle:

Principle #10Preliminary action

4Productivity

If peptide sequences are modified to improve V2R affinity, then potency increases, but immunogenicity may increase

Engineering Contradiction:

ImprovepotencyVSAvoidimmunogenicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies copying by creating multiple peptide variants (SEQ ID NO: 1 through SEQ ID NO: 6 and beyond) that copy the core pharmacophore structure of high-potency peptides while making selective amino acid substitutions. This allows optimization of V2R affinity (achieving 500-fold potency increase over tolvaptan) while monitoring and selecting variants with reduced immunogenicity profiles through iterative design and testing.

Inventive Principle:

Principle #26Copying

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 peptides demonstrate 500 times greater potency than tolvaptan in treating hyponatremia, with enhanced selectivity and reduced immunogenicity, suitable for long-term administration in various pathologies including hyponatremia, nephrogenic diabetes insipidus, and cancers.

Implementation Method 1

the peptides demonstrate 500 times greater potency than tolvaptan in treating hyponatremia, with enhanced selectivity

Methodology Applied

Scientific EffectReceptor binding:

Implementation Method 2

inhibiting cAMP production and inducing an aquaretic effect

Methodology Applied

Scientific EffectAquaretic effect:

Data Source

PatentUS12595288B2Vasopressin-2 receptor antagonist peptides and uses thereof

Publication Date: 2026.04.07 COMMISSARIAT A LENERGIE ATOMIQUE ET AUX ENERGIES ALTERNATIVES

AI summary

A peptide may include a sequence having 80% or more amino acid identity with the amino acid sequence of SEQ ID NO. 1, i.e., RPSX1CNLPVKPGPCX2GFFSAFYYSQKX3NKCHSFTYGGCAGNANRFSTX4EKCRRTC X5X6, wherein, X1 is the amino acid residue F or G, X2 is any amino acid residue, except a basic amino acid residue, X3 is the amino acid residue T or D, X4 is the amino acid residue I, L, or E, (i) X5 is V and X6 is G or (ii) X5 is G and X6 is V, and the amino acid located at position 39 is A. Such peptides may have various diagnostic and therapeutic uses.