Stabilized cyclic peptides as modulators of protein–protein interactions: promising strategies and biological evaluation

Cheng, Jiongjia; Zhou, Junlong; Kong, Lingyan; Wang, Haiying; Zhang, Yuchi; Wang, Xiaofeng; Liu, Guangxiang; Chu, Qian

doi:10.1039/d3md00487b

Cited by 11 publications

(2 citation statements)

References 133 publications

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“…To remedy this, macrocyclization, adding a ring of twelve or more atoms, has proved a successful strategy to 'pre-organize' a peptide for binding, by stabilizing the structures it adopts upon binding. This has included stabilization of specific secondary structures, and side-chain to side-chain 'staples' have been particularly successful in stabilizing α-helices 9 .…”

Section: Introductionmentioning

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: Introductionmentioning

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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show abstract

“…Kihlberg and co-workers have shown the importance of molecular chameleons in drug discovery and their role in protein–protein interactions 28 . This aspect was exhaustively discussed by Cheng et al 29 Protein–protein interactions (PPIs) control many basic biological pathways that are often misregulated in diseases 30 – 32 .…”

Section: Introductionmentioning

confidence: 99%

Influence of heterochirality on the structure, dynamics, biological properties of cyclic(PFPF) tetrapeptides obtained by solvent-free ball mill mechanosynthesis

Bak-Sypien,

Pawlak,

Paluch

et al. 2024

Sci Rep

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Cyclic tetrapeptides c(Pro-Phe-Pro-Phe) obtained by the mechanosynthetic method using a ball mill were isolated in a pure stereochemical form as a homochiral system (all L-amino acids, sample A) and as a heterochiral system with D configuration at one of the stereogenic centers of Phe (sample B). The structure and stereochemistry of both samples were determined by X-ray diffraction studies of single crystals. In DMSO and acetonitrile, sample A exists as an equimolar mixture of two conformers, while only one is monitored for sample B. The conformational space and energetic preferences for possible conformers were calculated using DFT methods. The distinctly different conformational flexibility of the two samples was experimentally proven by Variable Temperature (VT) and 2D EXSY NMR measurements. Both samples were docked to histone deacetylase HDAC8. Cytotoxic studies proved that none of the tested cyclic peptide is toxic.

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Stapled peptides as potential therapeutics for diabetes and other metabolic diseases

Nielipińska,

Rubiak,

Pietrzyk-Brzezińska

et al. 2024

Biomedicine & Pharmacotherapy

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Stabilized cyclic peptides as modulators of protein–protein interactions: promising strategies and biological evaluation

Abstract: Stabilized cyclic peptides present a promising class of molecules targeting pathological protein–protein interactions.

Cited by 11 publications

References 133 publications

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

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

Influence of heterochirality on the structure, dynamics, biological properties of cyclic(PFPF) tetrapeptides obtained by solvent-free ball mill mechanosynthesis

Stapled peptides as potential therapeutics for diabetes and other metabolic diseases

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