Abstract
Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as “undruggable”. Protein-DNA interactions, in particular, present a difficult challenge due to the repetitive nature of the B-DNA. Recent studies have provided several breakthroughs; however, a design methodology for these classes of inhibitors is still at its infancy. A dominant motif of these macromolecular interactions is an α-helix, raising possibilities that an appropriate conformationally-constrained α-helical peptide may specifically disrupt these interactions. Several methods for conformationally constraining peptides to the α-helical conformation have been developed, including stapling, covalent surrogates of hydrogen bonds and incorporation of unnatural amino acids that restrict the conformational space of the peptide. We will discuss these methods and several case studies where constrained α-helices have been used as building blocks for appropriate molecules. Unlike small molecules, the delivery of these short peptides to their targets is not straightforward as they may possess unfavorable cell penetration and ADME properties. Several methods have been developed in recent times to overcome some of these problems. We will discuss these issues and the prospects of this class of molecules as drugs.
Highlights
Protein-Protein (PPI) and Protein-DNA (PDI) interactions are one of the most fundamental interactions in the biological system
Short and α-helical peptides may be effectivePPIs functional of once a short unmodified peptide is synthesized much of its PPIs ability bind specific proteins involved in such interactions and capableinofisolation, effectively inhibiting or to biomolecules weakened,peptide as it tends adopt random-coil conformations rather than structured once a short is unmodified is to synthesized in isolation, much of its ability tothe bind specific and biologically relevant conformation
Work performed in the late 1990s and early 2000s first indicated that peptides with helical conformational preferences preferences might might be used to disrupt protein-protein interaction [25,26]
Summary
Protein-Protein (PPI) and Protein-DNA (PDI) interactions are one of the most fundamental interactions in the biological system. Due to their large size, antibodies are not ideally suited against some forms of solid tumors that require deep penetration Due to their smaller size and the possibilities of intracellular targeting, peptides hold promise for inhibiting PPIs and PDIs within the cell [5]. Short and α-helical peptides may be effectivePPIs functional of once a short unmodified peptide is synthesized much of its PPIs ability bind specific proteins involved in such interactions and capableinofisolation, effectively inhibiting or to PDIs. biomolecules weakened,peptide as it tends adopt random-coil conformations rather than structured once a short is unmodified is to synthesized in isolation, much of its ability tothe bind specific and biologically relevant conformation. Short helical peptides should be more resistant to proteolysis than their (due to their extended random-coil conformations) is their inherent susceptibility to proteases [7]. Given wider coverage as PPI inhibitors are more widely covered in the existing literature
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