Hydrogen Bond Surrogate‐Constrained Dynamic Antiparallel β‐Sheets

Reddy, Sravanthi S.; Pal, Somnath; Ghosh, Sudip; Prabhakaran, Erode N.

doi:10.1002/cbic.202100028

Cited by 3 publications

(5 citation statements)

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“…It is the only HBS model to mimic the 3 10 -helical turn 52 . Moreover, we have also shown that our HBS model has also been applied in studying dynamic β-sheet structures 53 . Thus, this HBS model is a generic replacement for H-bonds in a variety of turns (Figure 1).…”

Section: Introductionmentioning

confidence: 81%

Large Scale Synthesis of Native Turn and Helix Mimics Stabilized by a Generic Hydrogen Bond Surrogate

Prabhakaran

Pal

Kumar

et al. 2021

Preprint

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Short Turn and Helix mimics frequently represent molecular recognition surfaces perturbing bio-relevant protein-biomolecular interfaces. Generic methods that can stabilize short peptides into turns or helices by retaining all recognition elements, have tremendous applications in drug discovery. Here, a versatile modular synthetic protocol is presented for stabilizing turns and helices of different sizes by replacing their ring-closing hydrogen bonds with a generic three-carbon covalent surrogate. Two Fukuyama-Mitsunobu reactions insert the surrogate between desired residues in high yields and purity. Coupling with turn size-dependent oligopeptides containing both sterically restricted and non-coded residues, followed by macrolactamization yield a variety of stabilized turns. Short peptide extensions at the C-terminus of these turns yield stabilized 310-helices and α-helices. This solution-phase synthetic approach provides combinatorial access to libraries of stabilized turns and helices with all their native residues retained, in >100 mmole scales, in about one week per stabilized mimic, to technicians with postgraduate level training.

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Section: Introductionmentioning

confidence: 81%

Large Scale Synthesis of Native Turn and Helix Mimics Stabilized by a Generic Hydrogen Bond Surrogate

Prabhakaran

Pal

Kumar

et al. 2021

Preprint

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“…Therefore, developing a novel template to study this transition is essential for tackling the early stage of diseases caused by amyloid formation. A propyl‐linked HBS‐model dipeptide has been recently reported to study this transition [45] . The torque generated by the tertiary amide bond was employed to determine the equilibrium between the β‐sheet and non‐β‐ sheet conformations.…”

Section: Hbs‐model As Mimicry Of Different Secondary Structuresmentioning

confidence: 99%

“…Olefin [43] β-Hairpin NA TQTRAPGDEkITFG-NH 2 Thioether [44] β-Hairpin NA AG-iBu Propyl [45] β-sheet NA After helix, β-hairpin is the most abundant secondary structure of the proteins involved in several PPIs. [55,56,57] Apart from stabilizing different types of helices, the olefin HBS-model is also capable of mimicking the β-turn conformation.…”

Section: Afgve-iprmentioning

confidence: 99%

“…A propyllinked HBS-model dipeptide has been recently reported to study this transition. [45] The torque generated by the tertiary amide bond was employed to determine the equilibrium between the β-sheet and non-β-sheet conformations. The cis/ trans isomerization at the tertiary amide bond slowed down the interconversion between the ordered and disordered structures, which was observable in the NMR time scale.…”

Section: Afgve-iprmentioning

confidence: 99%

“…Olefin [43] β-Hairpin NA TQTRAPGDEkITFG-NH 2 Thioether [44] β-Hairpin NA AG-iBu Propyl [45] β-sheet NA…”

Section: Hbs As a π-Helix Mimicmentioning

confidence: 99%

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Impact of Hydrogen‐Bond Surrogate Model on Helix Stabilization and Development of Protein‐Protein Interaction Inhibitors

Pal

2023

ChemistrySelect

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Protein-protein interactions (PPIs) involved in several diseases are predominantly mediated through short helical peptides. Unlike small molecules, due to the extended surface, the chemically constrained peptides with proper helical conformation can modulate the PPIs and thus contribute to the future drug developments. Several model systems have been introduced in the past to induce the helical structure in short peptides. Incorporating the unnatural constraints by various protocols has been excellent in biasing helical conformation and improving the proteolytic stability and the cell permeability of peptides. Hydrogen-bond surrogate (HBS) is one of such well-known protocols to mimic helical surfaces in numerous peptide sequences. Unlike 'Stapled' peptides, HBSmodel replaces the main-chain i + 4!i hydrogen bonding interaction with a covalent surrogate and retains the side-chain functionality intact, which is beneficial for targeting multi-faced PPIs. This review focuses on the chemistry behind the development of the HBS-stabilized peptides, its biophysical characterizations, and numerous biological applications. Furthermore, this review will provide a broad overview of the HBS-model to attract chemical biologists to target multifaced 'difficult' PPIs.

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