Academic Journal
Electrophile Scanning Reveals Reactivity Hotspots for the Design of Covalent Peptide Binders
| العنوان: | Electrophile Scanning Reveals Reactivity Hotspots for the Design of Covalent Peptide Binders |
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| المؤلفون: | Nathalie M. Grob, Clint Remarcik, Simon L. Rössler, Jeffrey Y. K. Wong, John C. K. Wang, Jason Tao, Corey L. Smith, Andrei Loas, Stephen L. Buchwald, Dan L. Eaton, Magdalena Preciado López, Bradley L. Pentelute |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Biophysics, Biochemistry, Medicine, Genetics, Molecular Biology, Pharmacology, Biotechnology, Immunology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Information Systems not elsewhere classified, structural changes enacted, reactive modifiers via, major histocompatibility complex, electrophile scanning <, improve binding interactions, deep binding pockets, covalent peptide binders, identify reactivity hotspots, known peptide ligand, reactivity hotspots, known ligand, peptide sequence, enable binding, covalent mechanisms, well suited, typically present, target protein, strategy termed, results illustrate |
| الوصف: | Protein–protein interactions (PPIs) are intriguing targets in drug discovery and development. Peptides are well suited to target PPIs, which typically present with large surface areas lacking distinct features and deep binding pockets. To improve binding interactions with these topologies and advance the development of PPI-focused therapeutics, potential ligands can be equipped with electrophilic groups to enable binding through covalent mechanisms of action. We report a strategy termed electrophile scanning to identify reactivity hotspots in a known peptide ligand and demonstrate its application in a model PPI. Cysteine mutants of a known ligand are used to install protein-reactive modifiers via a palladium oxidative addition complex (Pd-OAC). Reactivity hotspots are revealed by cross-linking reactions with the target protein under physiological conditions. In a model PPI with the 9-mer peptide antigen VL9 and major histocompatibility complex (MHC) class I protein HLA-E, we identify two reactivity hotspots that afford up to 87% conversion to the protein–peptide conjugate within 4 h. The reactions are specific to the target protein in vitro and dependent on the peptide sequence. Moreover, the cross-linked peptide successfully inhibits molecular recognition of HLA-E by CD94–NKG2A possibly due to structural changes enacted at the PPI interface. The results illustrate the potential application of electrophile scanning as a tool for rapid discovery and development of covalent peptide binders. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://figshare.com/articles/journal_contribution/Electrophile_Scanning_Reveals_Reactivity_Hotspots_for_the_Design_of_Covalent_Peptide_Binders/24781864 |
| DOI: | 10.1021/acschembio.3c00538.s001 |
| الاتاحة: | https://doi.org/10.1021/acschembio.3c00538.s001 https://figshare.com/articles/journal_contribution/Electrophile_Scanning_Reveals_Reactivity_Hotspots_for_the_Design_of_Covalent_Peptide_Binders/24781864 |
| Rights: | CC BY-NC 4.0 |
| رقم الانضمام: | edsbas.B667ABCF |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acschembio.3c00538.s001 |
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