E-Selective Ring-Closing Metathesis in α-Helical Stapled Peptides Using Carbocyclic α,α-Disubstituted α-Amino Acids

Abstract

We present an E-selective ring-closing metathesis reaction in α-helical stapled peptides at positions i and i + 4. The use of two chiral carbocyclic α,α-disubstituted α-amino acids, (1S,3S)-Ac5c3OAll and (1R,3S)-Ac5c3OAll, provides a high E-selectivity of a ≤59:1 E:Z ratio, while mixtures with E:Z ratios of 2.1–0.5:1 were produced with standard acyclic (S)-(4-pentenyl)­alanine amino acids. A stapled octapeptide composed of (1S,3S)- and (1R,3S)-Ac5c3OAll amino acids showed a right-handed α-helical crystal structure.

Identification of a short ACE2-derived stapled peptide targeting the SARS-CoV-2 spike protein

“…As showed in Fig. 3 , right, the two multiplet signals at 5.66–5.57 ppm and 5.52–5.41 ppm of the terminal alkenyl hydrogen atoms were replaced by the diagnostic broad singlet signal at 5.13 ppm attributable to the newly formed internal double bond, which showed a preference for the Z isomeric form, as reported for other RCM of ( S )-(4-pentenyl)Ala at positions i and i +4 present in the literature [ 41 , 42 ].

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Development of a Double-Stapled Peptide Stabilizing Both α-Helix and β-Sheet Structures for Degrading Transcription Factor AR-V7

“…Peptide drugs have historically faced challenges, including issues such as poor blood stability and limited cell membrane penetration. , However, recent advancements in peptide drug delivery systems and peptide modification chemistry have revitalized interest in the clinical application of peptide drugs. − Notably, progress in peptide modification chemistry has opened up new avenues, with peptide stapling emerging as a highly promising strategy to enhance peptide stability and improve their ability to penetrate cell membranes. − Among various peptide stapling chemistries, the all-hydrocarbon peptide stapling triggered by solid-phase ring-closing metathesis (RCM) reaction has garnered significant attention. , Hydrocarbon-stapled peptides hold great promise as a therapeutic modality for a range of diseases, including cancer, viral infections, and autoimmune disorders. − They offer several advantages over traditional peptide molecules and large protein molecules, including enhanced target specificity, improved cell permeability, and increased oral bioavailability. − Remarkably, ALRN-6924, a representative stapled peptide drug, has progressed into clinical trials for the treatment of advanced solid tumors and lymphomas. − …”

“… 7 − 11 Among various peptide stapling chemistries, the all-hydrocarbon peptide stapling triggered by solid-phase ring-closing metathesis (RCM) reaction has garnered significant attention. 12 , 13 Hydrocarbon-stapled peptides hold great promise as a therapeutic modality for a range of diseases, including cancer, viral infections, and autoimmune disorders. 14 − 17 They offer several advantages over traditional peptide molecules and large protein molecules, including enhanced target specificity, improved cell permeability, and increased oral bioavailability.…”

Comparative Analysis of Cyclization Techniques in Stapled Peptides: Structural Insights into Protein–Protein Interactions in a SARS-CoV-2 Spike RBD/hACE2 Model System

“…In vivo efficacy was validated via the intravenous administration of i , i + 4 stabilized helical peptides bearing two S-pentenyl alanine residues (S5) in a murine model of cancer [ 31 , 32 ]. From a synthesis perspective, this technique offers on-resin cyclization and is orthogonal to amino acid-protecting groups but requires synthetically challenging α,α-disubstituted building blocks [ 33 ] to yield two double-bond isomers [ 34 ]. Because enhanced hydrophobicity can also lead to aggregation, a more hydrophilic thiol-ene stapling technique has recently been compared with hydrocarbon stapled analogues [ 35 ].…”