Bridged bicyclic peptides: Structure and function

Thombare, Varsha J.; Hutton, Craig A.

doi:10.1002/pep2.24057

Cited by 14 publications

(10 citation statements)

References 138 publications

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“…We also considered rigidification of the cyclic peptide scaffold through the formation of a transannular bridge, a structural feature that has been found in both natural and synthetic peptides to improve their activity. − To achieve this, we first identified two amino acids in KD2, Val3 and Arg9, that do not participate in intramolecular interactions or binding interaction with K-Ras (Figure a). By replacing these two amino acids with two cysteines or a combination of azidohomoalanine and propargylglycine, we synthesized two bicyclic variants of KD2 (Figure b).…”

Section: Results and Discussionmentioning

confidence: 99%

GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf

Zhang

Gao

et al. 2020

ACS Cent. Sci.

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We report the identification of three cyclic peptide ligands of K-Ras(G12D) using an integrated in vitro translation–mRNA display selection platform. These cyclic peptides show preferential binding to the GTP-bound state of K-Ras(G12D) over the GDP-bound state and block Ras-Raf interaction. A co-crystal structure of peptide KD2 with K-Ras(G12D)·GppNHp reveals that this peptide binds in the Switch II groove region with concomitant opening of the Switch II loop and a 40° rotation of the α2 helix, and that a threonine residue (Thr10) on KD2 has direct access to the mutant aspartate (Asp12) on K-Ras. Replacing this threonine with non-natural amino acids afforded peptides with improved potency at inhibiting the interaction between Raf1-RBD and K-Ras(G12D) but not wildtype K-Ras. The union of G12D over wildtype selectivity and GTP state/GDP state selectivity is particularly desirable, considering that oncogenic K-Ras(G12D) exists predominantly in the GTP state in cancer cells, and wildtype K-Ras signaling is important for the maintenance of healthy cells.

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Section: Results and Discussionmentioning

confidence: 99%

GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf

Zhang

Gao

et al. 2020

ACS Cent. Sci.

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“…Because the catch‐all definition of a loop precludes categorization by structure, we will discuss peptides based on the chemistries used for peptide cyclization. Recent reviews by Fairlie, Hutton, and coworkers highlight many natural and synthetic peptides that bind to proteins, including several that competitively inhibit PPIs . We will also mention novel chemical approaches that have been applied with the intent of stabilizing non‐regular structures, even in the absence of structures.…”

Section: Non‐regular Peptidesmentioning

confidence: 99%

Bent into shape: Folded peptides to mimic protein structure and modulate protein function

2020

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“…Bridged carbocycle systems, including bridged bicyclic and tricyclic carbocycles, are ubiquitous in numerous families of biologically active natural products and unnatural bioactive compounds because of their versatile reactivity . Efficient construction of bridged carbocycles has therefore attracted considerable interest from synthetic chemists, and it has prompted the development of numerous synthetic strategies .…”

Section: Introductionmentioning

confidence: 99%

Theoretical Study of Ruthenium(0)-Catalyzed Transfer Hydrogenative Cycloaddition of Cyclohexadiene and Norbornadiene with 1,2-Diols to Form Bridged Carbocycles

Tian

et al. 2019

J. Org. Chem.

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The recent success of Krische et al. (Angew. Chem., Int. Ed.20175614667–14671) in achieving a ruthenium(0)-catalyzed transfer hydrogenative cycloaddition of 1,2-diols with cyclohexadiene and norbornadiene in excellent yield with exo- and diastereoselectivity represents an exciting development in the synthesis of bridged carbocycles. In the present work, the possible catalytic mechanisms and origin of the exo- and diastereoselectivity for cyclohexadiene and norbornadiene were studied in detail by density functional theory calculations. The theoretical results indicate that the exoselective pathway for the cyclohexadiene substrate proceeds by a novel two-step successive C–C coupling, while the endoselective pathway undergoes the C–C coupling reaction in a conventional concerted manner. The origin of the preferential chemoselectivity of dione–cyclohexadiene C–C coupling over aromatization to benzene was investigated. Aromatization to benzene is unfavorable because of the large distortion energy of the three-membered ring in the transition state of hydrogen migration. From distortion/interaction analysis, for norbornadiene, the distortion energy plays the main role in determining the exoselectivity.

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Bridged bicyclic peptides: Structure and function

Cited by 14 publications

References 138 publications

GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf

GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf

Bent into shape: Folded peptides to mimic protein structure and modulate protein function

Theoretical Study of Ruthenium(0)-Catalyzed Transfer Hydrogenative Cycloaddition of Cyclohexadiene and Norbornadiene with 1,2-Diols to Form Bridged Carbocycles

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