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

Department of Biophysics, Bose Institute, P1/12 CIT Scheme VII M, Kolkata 700054, India
Author to whom correspondence should be addressed.
Biomedicines 2018, 6(4), 118;
Received: 7 August 2018 / Revised: 13 September 2018 / Accepted: 14 September 2018 / Published: 18 December 2018
(This article belongs to the Special Issue Discovery and Development of Constrained Peptide Ligands)
PDF [1415 KB, uploaded 18 December 2018]


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. View Full-Text
Keywords: helix; synthetic transcription factor; peptide helix; synthetic transcription factor; peptide

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Roy, S.; Ghosh, P.; Ahmed, I.; Chakraborty, M.; Naiya, G.; Ghosh, B. Constrained α-Helical Peptides as Inhibitors of Protein-Protein and Protein-DNA Interactions. Biomedicines 2018, 6, 118.

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