Aziridine Compounds for Cross-Linking Undruggable Target Proteins
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Solution Overview
Problem
Current small molecule drug discovery methods are ineffective for targeting approximately 90% of human proteins, known as 'undruggable' targets, limiting the development of modulators for medically important proteins.
Innovation Solution
Development of compounds capable of forming complexes and/or crosslinking to target proteins, represented by specific structural formulas, including various substituents and isotopically enriched hydrogen, to create novel molecular modalities for modulating protein function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If conventional small molecule drugs are used to target proteins, then drugs can effectively bind to functionally important pockets on target proteins, but only about 10% of human proteins are targetable by small molecules
Solution Approach 1:
The patent employs parameter changes by utilizing non-canonical amino acids with unique chemical properties (such as photoreactive groups, biotin, and other functional moieties) that differ from the 20 canonical amino acids. These parameter changes in amino acid chemistry enable the formation of complexes with undruggable targets that cannot be targeted by conventional small molecules, thereby expanding protein targetability while maintaining reliable modulation of protein function.
2Adaptability or versatility
If new molecular modalities are developed to target undruggable proteins, then the range of targetable proteins expands, but the complexity of compound structure and synthesis increases
Solution Approach 1:
The patent uses photoaffinity labeling as an intermediary mechanism. The compounds contain photoreactive groups that act as intermediaries to form covalent bonds with target proteins upon light irradiation. This intermediary approach allows the compounds to first bind reversibly to undruggable targets (which lack traditional drug-binding pockets) and then form stable covalent complexes, thereby expanding targetability without requiring overly complex molecular structures.
Solution Approach 2:
The patent employs composite materials by combining non-canonical amino acid residues with various functional groups (photoreactive groups, biotin, fluorophores, etc.) within peptide and protein structures. These composite structures integrate multiple functionalities into single molecules, enabling them to target undruggable proteins while maintaining manageable structural complexity through modular design.
Data Source
AI summary
The invention features compounds containing an aziridine moiety and methods of synthesizing the same. The compounds may be bound to a monovalent organic moiety and may be used to bind to a target (e.g., a target protein), for example, by cross-linking the target. In some embodiments, the monovalent organic moiety is capable of binding to a presenter protein. Also disclosed are complexes containing the compounds (e.g., presenter protein/compound complexes, compound/target protein complexes, or tri-complexes). Methods of forming the complexes and methods of using the compounds and complexes to modulate biological processes are also disclosed.