Helix stabilization by stapled N-capping box

Pham, Thanh K.; Kim, Young Woo

doi:10.1016/j.bioorg.2020.104024

Cited by 7 publications

(2 citation statements)

References 19 publications

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“…The stabilization of peptide helices has been a long-standing goal of peptide chemists, and a range of macrocyclic N-capping strategies have been explored to achieve this (Figure S14) 46 . Most similar to our heliat motif is a rationally designed ring closing metathesis strategy [47][48] to mimic the N-capping box, which also produced a helix-stabilizing macrocycle of 15 atoms. However, such rational N-capping methods require significant synthesis expertise, specialist reagents, often both.…”

Section: Discussionmentioning

confidence: 99%

Mixed stereochemistry macrocycle acts as a helix-stabilizing peptide N-cap

Hink,

Aduriz-Arrizabalaga,

Lopez

et al. 2024

Preprint

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Interactions between proteins and α-helical peptides are abundant in the human cell. Many of these interactions are linked to disease and have been the focus of drug discovery campaigns. However, the large interfaces formed between multiple turns of α-helix and a binding protein represent a significant challenge to inhibitor discovery. Modified peptides featuring helix-stabilizing macrocycles have shown promise as inhibitors of these interactions. Here, we tested the ability of N-terminal to side-chain thioether-cyclized peptides to inhibit the α-helix binding protein Mcl-1, by screening a trillion-scale peptide library using RaPID technology. The top enriched peptides were lariats, featuring a small, four amino acid N-terminal macrocycle followed by a short linear sequence that resembled the natural α-helical Mcl-1 ligands. These ‘Heliats’ (Helical lariats) bound Mcl-1 with mid-nM affinity, and inhibited the interaction between Mcl-1 and a natural peptide ligand. Macrocyclization was found to stabilize α-helical structures, and significantly contribute to affinity and potency. Yet, the 2nd and 3rd positions within the macrocycle were permissible to sequence variation, so that a minimal macrocyclic motif, of an N-acetylated D-phenylalanine at the 1st position thioether connected a cysteine at the 4th, could be grafted into a natural peptide and stabilize helical conformations. We found that D-stereochemistry is more helix-stabilizing than L- at the 1st position in the motif, as the D-amino acid can utilize polyproline II torsional angles that allow for more optimal intrachain hydrogen bonding. This mixed stereochemistry macrocyclic N-cap is synthetically accessible, requiring only minor modifications to standard solid-phase peptide synthesis, and its compatibility with RaPID peptide screening can provide ready access to helix-focused peptide libraries for de novo inhibitor discovery.

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Section: Discussionmentioning

confidence: 99%

Mixed stereochemistry macrocycle acts as a helix-stabilizing peptide N-cap

Hink,

Aduriz-Arrizabalaga,

Lopez

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…204,205 This reaction is among the most commonly applied to peptides for stabilizing secondary structures, in particular for α-helices. [206][207][208][209] Furthermore, it has also been employed to stabilize or mimic other motifs, such as β-sheets, 210 β-turns, 211,212 polyproline II helices, 213 3 10 helices, 214,215 N-capping boxes, 216 and disulfide bridges. 217,218 The generated alkenes are generally more conformationally restricted than disulfides, but this is not always the case.…”

Section: Rsc Medicinal Chemistrymentioning

confidence: 99%