Beyond the Protein: Manipulating Proteoforms with Chemical Tools

Descripción del proyecto

Actuar de forma selectiva sobre formas proteicas específicas en las células

El cuerpo humano alberga unos veinte mil genes codificadores de proteínas, pero cada gen puede dar lugar a más de una proteoforma. Esta diversidad de proteínas aumenta a través de procesos complejos como el corte y empalme alternativo del ARN mensajero y las modificaciones postraduccionales. Los cambios en proteínas específicas se han asociado con el cáncer y las enfermedades neurodegenerativas, por lo que es fundamental comprender los mecanismos que subyacen a estos procesos. En el proyecto PROTEOFORMER, financiado por el Consejo Europeo de Investigación, se pretende desarrollar herramientas químicas para manipular con precisión determinadas proteoformas dentro de las células. La investigación se centrará en un receptor cerebral implicado en la enfermedad de Parkinson y un regulador clave de la neuroinflamación. Los investigadores inhibirán o inducirán cambios selectivos de proteoforma añadiendo cargas químicas funcionales directamente a las proteoformas elegidas.

Objetivo

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.