Peptidomimetic Compounds for Proteolysis Resistance
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Solution Overview
Problem
Current methods for developing peptide or peptide-mimetic active ingredients face challenges such as low metabolic stability, poor absorption, rapid elimination, and lack of selectivity, along with difficulties in interacting effectively with protein domains, particularly for proline-rich motifs like the PPII helix, which are associated with various diseases including bacterial infections, neurodegenerative diseases, and tumors.
Innovation Solution
Development of compounds with a saturated or unsaturated central seven-membered ring structure that can mimic proline-rich peptides, specifically interacting with PRM binding domains as receptor ligands, thereby mimicking or blocking biological effects, and having improved metabolic stability and selectivity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide active ingredients are used as pharmaceuticals, then they can perform biological functions as receptor ligands, but they exhibit low metabolic stability due to proteolysis in the gastrointestinal tract and serum
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of peptides through peptidomimetic design, replacing peptide bonds with non-hydrolyzable isosters and incorporating conformational constraints to maintain biological activity while resisting proteolytic degradation. This transforms the molecular parameters to achieve metabolic stability without losing receptor binding capability.
Solution Approach 2:
The patent employs composite materials by creating hybrid molecules that combine peptide-like functional groups with non-peptide structural elements. These composite peptidomimetics integrate the bioactivity of peptides with the stability of small molecules, forming a new class of compounds that exhibit both receptor affinity and metabolic resistance.
2Reliability
If peptide active ingredients are used as pharmaceuticals, then they can perform biological functions, but they exhibit poor absorption after oral administration due to high molecular mass
Solution Approach 1:
The patent applies segmentation by dividing the peptide structure into essential functional segments and non-essential bulk segments. The core pharmacophore is retained while removing or reducing unnecessary amino acid sequences, creating truncated peptidomimetics that maintain activity but have lower molecular mass for improved oral absorption.
Solution Approach 2:
The patent changes molecular parameters by replacing peptide bonds with non-hydrolyzable linkers and incorporating bioisosteric substitutions that reduce molecular weight while preserving three-dimensional structure and receptor interaction capabilities, thereby improving oral bioavailability.
3Reliability
If peptide active ingredients are used as pharmaceuticals, then they can perform biological functions, but they exhibit rapid excretion by the liver and kidneys
Solution Approach 1:
The patent modifies molecular parameters by introducing conformational constraints through cyclic structures, bridging groups, and rigidifying elements that reduce flexibility and molecular recognition by renal and hepatic clearance mechanisms. These structural changes decrease the rate of excretion while maintaining biological activity.
Solution Approach 2:
The patent creates composite peptidomimetic structures that combine peptide pharmacophores with non-peptide scaffolds having altered pharmacokinetic properties. These hybrid molecules exhibit reduced susceptibility to renal filtration and hepatic metabolism, extending duration of action.
4Reliability
If peptide active ingredients are used as pharmaceuticals, then they can perform biological functions, but they exhibit lack of selectivity due to interaction with different receptors
Solution Approach 1:
The patent applies local quality by optimizing specific regions of the peptidomimetic molecule that interact with the target receptor binding site. By modifying local chemical properties, stereochemistry, and spatial arrangement of key functional groups, the patent enhances selectivity for the intended receptor while reducing off-target interactions.
Solution Approach 2:
The patent changes molecular parameters including stereochemical configuration, bond angles, and three-dimensional conformation to achieve precise geometric complementarity with the target receptor. These parameter optimizations increase binding specificity and reduce cross-reactivity with unrelated receptors.
Data Source
AI summary
The invention relates to compounds of general formula (I), which can be used particularly as structural mimetics of proline-rich peptides and are therefore capable of binding PRM binding domains (proline-rich-motif binding domains) of proteins. The invention also relates to the use of said compounds as pharmaceutical active agents and the use of these pharmaceutical active agents for treating bacterial diseases, neurodegenerative diseases and tumours.