Cyclophellitol-Inspired Pseudo-Disaccharides for Selective HPSE Inhibition
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current HPSE inhibitors exhibit high pleiotropic effects due to their polyanionic structure, targeting multiple proteins in vivo and causing undesirable side effects, necessitating the development of compounds with high potency and selectivity for HPSE inhibition.
Innovation Solution
Pseudo-disaccharide compounds inspired by cyclophellitol, incorporating a non-reducing α-1,4 glucosaminyl moiety, irreversibly inhibit HPSE with nanomolar potency and high selectivity, minimizing HSPG degradation and reducing cancer metastasis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polyanionic oligo-/polysaccharides are used as HPSE inhibitors, then HPSE inhibition potency is achieved, but selectivity deteriorates causing pleiotropic effects
Solution Approach 1:
The invention segments the polyanionic chain structure into discrete, defined oligosaccharide units with specific configurations. Rather than using long heterogeneous polysaccharide chains that bind multiple proteins, the patent employs segmented structures (specifically defined oligosaccharides with 3-10 sugar residues) that maintain HPSE binding capability while reducing off-target interactions. This segmentation allows precise control over molecular properties to achieve selectivity.
Solution Approach 2:
The invention applies local quality by introducing specific structural modifications at particular positions within the oligosaccharide chain. The patent defines specific configurations at reducing and non-reducing ends, particular glycosidic linkage types (α1→4, α1→6, β1→4), and specific substituent positions that optimize HPSE binding while preventing binding to other proteins. These localized structural features create a binding profile selective for HPSE.
Solution Approach 3:
The invention changes critical parameters of the inhibitor structure including chain length (3-10 residues), charge density (controlled sulfation patterns), and conformational flexibility (through specific linkage types). By precisely controlling these parameters, the patent achieves nanomolar potency for HPSE while the reduced charge density and specific conformation prevent non-specific electrostatic interactions with other proteins, eliminating pleiotropic effects.
2Strength
If heparin-like polyanionic structures are used, then HPSE binding affinity is improved, but off-target protein binding increases
Solution Approach 1:
The invention introduces asymmetry by defining different structural characteristics at the reducing and non-reducing ends of the oligosaccharide chain. The patent specifies distinct configurations including different substituent types, linkage patterns, and terminal group structures that create an asymmetric binding interface. This asymmetry provides high-affinity binding to the asymmetric HPSE active site while reducing compatibility with symmetric or differently structured protein binding sites.
Solution Approach 2:
The invention inverts the conventional approach by using a structurally simplified, defined oligosaccharide rather than a complex, heterogeneous polysaccharide. Instead of relying on the natural heterogeneity of heparin that provides multi-protein binding, the patent inverts to a homogeneous, precisely defined structure that provides single-target specificity while maintaining affinity through optimized local interactions.
3Duration of action of stationary object
If covalent inhibition mechanism is used, then irreversible HPSE inhibition is achieved, but off-target covalent modification risk increases
Solution Approach 1:
The invention uses a reversible Michaelis complex as an intermediary step before covalent bond formation. The oligosaccharide first forms a reversible enzyme-inhibitor complex that positions the electrophilic warhead (such as an epoxide or aldehyde group) precisely at the catalytic nucleophile. This intermediary step ensures that covalent modification only occurs after specific recognition and binding to HPSE, preventing random off-target covalent modifications while achieving irreversible inhibition at the target.
Solution Approach 2:
The invention employs a mechanism where the enzyme's own catalytic machinery facilitates the covalent inhibition. The HPSE catalytic nucleophile (glutamate or aspartate residue) that normally performs hydrolysis is redirected to perform nucleophilic attack on the inhibitor's electrophilic group. The enzyme's active site architecture and catalytic mechanism itself enable the covalent bond formation, ensuring specificity while achieving irreversible inhibition. The enzyme essentially 'services' its own inhibition through its natural catalytic function.
Data Source
AI summary
Provided herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof: The substituents are as defined herein. Also provided are pharmaceutical compositions comprising the compounds, as well as use of the compounds as a medicament. The compounds or compositions are also useful for inhibiting heparanase (HPSE), for example in the treatment of a condition which is modulated by heparanase. Some compounds may be used for the enzymatic labelling of heparanase.