RESUMEN
Chemoselective reactions for amide bond formation have transformed the ability to access synthetic proteins and other bioconjugates through ligation of fragments. In these ligations, amide bond formation is accelerated by transient enforcement of an intramolecular reaction between the carboxyl and the amine termini of two fragments. Building on this principle, we introduce an aldehyde capture ligation that parlays the high chemoselective reactivity of aldehydes and amines to enforce amide bond formation between amino acid residues and peptides that are difficult to ligate by existing technologies.
Asunto(s)
Aldehídos/química , Amidas/síntesis química , Péptidos/síntesis química , Amidas/química , Aminas/química , Estructura Molecular , Péptidos/químicaRESUMEN
ß-Strands are a fundamental component of protein structure, and these extended peptide regions serve as binding epitopes for numerous protein-protein complexes. However, synthetic mimics that capture the conformation of these epitopes and inhibit selected protein-protein interactions are rare. Here we describe covalent and noncovalent ß-hairpin mimics of an extended strand region mediating the Tcf4/ß-catenin interaction. Our efforts afford a rationally designed lead for an underexplored region of ß-catenin, which has been the subject of numerous ligand discovery campaigns.
Asunto(s)
Péptidos Cíclicos/metabolismo , Unión Proteica/efectos de los fármacos , Factor de Transcripción 4/metabolismo , beta Catenina/metabolismo , Secuencia de Aminoácidos , Escherichia coli/química , Proteínas de Escherichia coli/metabolismo , Péptidos Cíclicos/química , Conformación ProteicaRESUMEN
Over the past decade, protein-protein interactions (PPIs) have gone from being neglected as 'undruggable' to being considered attractive targets for the development of therapeutics. Recent advances in computational analysis, fragment-based screening, and molecular design have revealed promising strategies to address the basic molecular recognition challenge: how to target large protein surfaces with specificity. Several systematic and complementary workflows have been developed to yield successful inhibitors of PPIs. Here we review the major contemporary approaches utilized for the discovery of inhibitors and focus on a structure-based workflow, from the selection of a biological target to design.