Beyond the Protein: Manipulating Proteoforms with Chemical Tools

The human body can synthesize ~70’000 different proteins. These proteins diversify into millions of proteoforms, e.g., by associating into complexes or acquiring functionalities called post-translational modifications (PTMs). Distinct proteoforms are often found in different cell types and have diverse functions. Dysregulation of specific proteoforms is associated with many diseases, including neurodegeneration or cancers, highlighting the need for their study and modulation. Despite these needs, most drug-like molecules are designed to indiscriminately activate, inhibit, or destroy a target protein—they are blind to the localization or function of different proteoforms.PROTEOFORMER goes beyond the protein by developing chemical tools for manipulating specific protein forms. In two parallel initiatives, PROTEOFORMER will:(1) Target a specific proteoform of the muscarinic acetylcholine receptor—relevant to Parkinson’s disease treatment—dissecting its function and laying the groundwork for new therapies.(2) Modify post-translational modifications of matrix metalloproteinase-2—a key regulator of neuroinflammation—aiming to unravel their so-far-elusive function.PROTEOFORMER offers tailored reagents that (i) recognize the protein target, (ii) bring a reactive group to the target’s surface, and (iii) attach molecular cargo to the protein via a proximity-induced reaction. It rethinks this ‘ligand-directed chemistry’ by introducing functional, proteoform-manipulating cargo:(1) A blocker of a partner protein, enabling proteoform-selective inhibition within a cell-specific complex.(2) A post-translational modification or its eraser, enabling on-demand switching between proteoforms with newly developed proximity-driven chemical reactions.PROTEOFORMER develops new chemistry for manipulating proteoforms beyond current capabilities. These general concepts represent a chemical solution to long-standing challenges in biology that are intractable with traditional methods.