2023
DOI: 10.1021/acscentsci.2c01462
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Stretching Peptides to Generate Small Molecule β-Strand Mimics

Abstract: Advances in the modulation of protein−protein interactions (PPIs) enable both characterization of PPI networks that govern diseases and design of therapeutics and probes. The shallow protein surfaces that dominate PPIs are challenging to target using standard methods, and approaches for accessing extended backbone structures are limited. Here, we incorporate a rigid, linear, diyne brace between side chains at the i to i+2 positions to generate a family of low-molecular-weight, extended-backbone peptide macrocy… Show more

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Cited by 12 publications
(5 citation statements)
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“…Aberrant PPIs between β-sheet domains are implicated in several diseases, making them attractive targets for pharmacologic intervention. , While some of these interfaces involve multiple strands from each protein (β-sheet face interactions), many targets engage only a single strand of an interacting partner. This has motivated efforts toward β-strand mimics that do not require an auxiliary strand to stabilize an extended conformation. Such designs may have the added benefit of reduced molecular weight and potentially enhanced membrane permeability relative to template-based approaches.…”
Section: β-Strand/sheet Stabilization Through Peptide N-heteroatom Su...mentioning
confidence: 99%
“…Aberrant PPIs between β-sheet domains are implicated in several diseases, making them attractive targets for pharmacologic intervention. , While some of these interfaces involve multiple strands from each protein (β-sheet face interactions), many targets engage only a single strand of an interacting partner. This has motivated efforts toward β-strand mimics that do not require an auxiliary strand to stabilize an extended conformation. Such designs may have the added benefit of reduced molecular weight and potentially enhanced membrane permeability relative to template-based approaches.…”
Section: β-Strand/sheet Stabilization Through Peptide N-heteroatom Su...mentioning
confidence: 99%
“…Significantly, epimerisation of the staple amino acids was observed during synthesis. Dawson and co‐workers have also reported incorporation of an i , i +2 diyne constraint to construct stretched β‐strand mimics [21] . The rigid diyne brace allowed the peptides to adopt stable conformations in solution, and could be generated in excellent conversions.…”
Section: Introductionmentioning
confidence: 99%
“…Dawson and co‐workers have also reported incorporation of an i , i +2 diyne constraint to construct stretched β‐strand mimics. [21] The rigid diyne brace allowed the peptides to adopt stable conformations in solution, and could be generated in excellent conversions. Notably, this reported staple type differs from this work, exhibiting different amino acid positioning, peptide secondary structure and finally does not include α‐methyl carbons.…”
Section: Introductionmentioning
confidence: 99%
“…[15][16] Whilst, peptides which adopt an α-helical bound state have received considerable attention cyclization being a profitable strategy to address these limitations [15][16][17][18] -β-strand-mediated interactions are less well studied. 13,19 A further feature of short recognition peptides is that they are often intrinsically disordered 20 and undergo disorder-order transitions, e.g., to form α-helices 21 or β-strands 22 on PPI formation. The association binding kinetics of coupled folding and binding are influenced by the larger hydrodynamic radius, flexibility and folding propensity of IDPs in comparison to folded proteins, alongside the abundance of exposed charged residues which are often associated with encounter complex formation.…”
Section: Introductionmentioning
confidence: 99%