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Peptido 26-26

The document discusses the design and stabilization of helical peptides using hydrocarbon stapling and ring closing metathesis (RCM). It highlights key considerations such as chain length and staple position, and reviews various stabilized structures that enhance peptide binding to RNAs. The findings indicate that specific configurations and cross-link lengths significantly improve helicity and cellular activity of stapled peptides.

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7 views1 page

Peptido 26-26

The document discusses the design and stabilization of helical peptides using hydrocarbon stapling and ring closing metathesis (RCM). It highlights key considerations such as chain length and staple position, and reviews various stabilized structures that enhance peptide binding to RNAs. The findings indicate that specific configurations and cross-link lengths significantly improve helicity and cellular activity of stapled peptides.

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havadese.tarikhi
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Chemical Reviews pubs.acs.

org/CR Review

Figure 26. Design of bis-alkylated, hydrocarbon stapled peptides. A) Chain length, staple position, and stereochemistry are key considerations for
generating helical hydrocarbon stapled peptides. B) Schematic of peptide functionalization using ring closing metathesis.

Figure 27. Stapled peptides derived from BH3 domains. A) Primary sequences of peptides derived from BAK, BID, and MCL-1 showing staple
positions in designer peptides. B) Representative helix from MCL-1 SAHBD. Hydrocarbon staple is highlighted in yellow, and key interacting
residues are shown. C) Crystal structure of SAHBD bound to MCL-1 with interacting residues labeled. PDB 3MK8.384

Gly6/Lys7, form the β-turns (Figure 25B,C). L50 was shown suggested a predominantly 310-helix conformation, due to the i,
to inhibit miR-21 formation both in vitro and in cells. Other i+3 hydrogen bonding pattern and the torsional angles. While
miRNAs, such as pre-miRNA-20b, have also been targeted the helical character showed little change with substitution and
with stabilized β-hairpins, though with relatively weak metathesis, the bioorthogonality and hydrophobic nature of
affinity.378 A deeper examination of stabilized β-hairpins the cross-link was an attractive strategy to stabilize α-helical
binding RNAs, along with other stabilized structures binding conformations.
RNAs, have been covered in this excellent review by Pal and ‘t Schafmeister et al. further investigated the potential of RCM
Hart.379 for peptide stabilization by using disubstituted amino acids
with both R and S configuration and various side chain length
3.4. Stabilized Helical Secondary Structures Using
Hydrocarbon Stapling to determine which combinations would give the best yield as
well as the most stabilizing effect on helix formation (Figure
A significant breakthrough in helical stabilization came with 26).319 Within a specific model system, they discovered that
the application of ring closing metathesis for peptide for i, i+7 staple placement between R- and S-amino acids, at
stabilization as it introduced a stable, nonpolar stabilizing least a 9-carbon cross-link was required to observe appreciable
cross-link that could improve cellular uptake and activity of conversion of an RNase A derived peptide to the stapled
stapled peptides. Blackwell and Grubbs first reported the use of product. For i, i+4, using Ri, Ri+4 and Si, Si+4 α-methyl amino
the ring closing metathesis (RCM) reaction to stabilize peptide acids, 8 carbons was the minimum length required for near
helices in 1998, where they incorporated serine or homoserine complete conversion. From this library they concluded that an
O-allyl ether residues (Figure 23C).318 The sequence, even i, i+7 staple with R,S paired configuration and an 11-carbon
prior to substitution with the olefinic residues, showed helical cross-link resulted in the greatest increase in helicity, followed
character, likely due to the prevalence of amino acids with high by the R,S paired i, i+7 staple with 12-carbon cross-link and S,S
propensity for helix formation. An X-ray crystal structure paired i, i+4 staple with 8-carbon cross-link.380 The proteolytic
Z https://doi.org/10.1021/acs.chemrev.4c00423
Chem. Rev. XXXX, XXX, XXX−XXX

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