Constrained α-Helical Peptides as Inhibitors of Protein-Protein and Protein-DNA Interactions.

摘要: Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs targeted toward enzymes extracellular receptors. Protein-protein interactions have long been considered as “undruggable”. Protein-DNA in particular, present a difficult challenge due to the repetitive nature of B-DNA. Recent studies provided several breakthroughs; however, design methodology these classes inhibitors is still at its infancy. A dominant motif macromolecular an α-helix, raising possibilities that appropriate conformationally-constrained α-helical peptide may specifically disrupt interactions. Several methods conformationally constraining peptides conformation developed, including stapling, covalent surrogates hydrogen bonds incorporation unnatural amino acids restrict conformational space peptide. We will discuss case where constrained α-helices used building blocks molecules. Unlike small molecules, delivery short their not straightforward they possess unfavorable cell penetration ADME properties. developed recent times overcome some problems. issues prospects this class molecules drugs.