The reactivity and conformational control of cyclic tetrapeptides derived from aziridine-containing amino acids

Chung, Benjamin K. W.; White, Christopher J. Branford; Scully, Conor C. G.; Yudin, Andrei K.

doi:10.1039/c6sc01687a

Cited by 20 publications

(12 citation statements)

References 52 publications

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“…Again, a similar conformation is observed for the recently isolated Endolide A, albeit the two trans ‐peptide bonds are of the opposite orientation . Examples of 13‐membered CTPs bearing non‐cyclic β‐AAs, more flexible than 2‐Abz, have proven conformationally homogeneous in some instances, but heterogeneous in others . Here we find, that 2‐Abz containing CTPs bear the all trans ‐configuration in both solution and crystal states.…”

Section: Resultssupporting

confidence: 82%

Crystal and NMR Structures of a Peptidomimetic β‐Turn That Provides Facile Synthesis of 13‐Membered Cyclic Tetrapeptides

Cameron

Squire

Edwards

et al. 2017

Chemistry An Asian Journal

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Herein we report the unique conformations adopted by linear and cyclic tetrapeptides (CTPs) containing 2-aminobenzoic acid (2-Abz) in solution and as single crystals. The crystal structure of the linear tetrapeptide H N-d-Leu-d-Phe-2-Abz-d-Ala-COOH (1) reveals a novel planar peptidomimetic β-turn stabilized by three hydrogen bonds and is in agreement with its NMR structure in solution. While CTPs are often synthetically inaccessible or cyclize in poor yield, both 1 and its N-Me-d-Phe analogue (2) adopt pseudo-cyclic frameworks enabling near quantitative conversion to the corresponding CTPs 3 and 4. The crystal structure of the N-methylated peptide (4) is the first reported for a CTP containing 2-Abz and reveals a distinctly planar 13-membered ring, which is also evident in solution. The N-methylation of d-Phe results in a peptide bond inversion compared to the conformation of 3 in solution.

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Section: Resultssupporting

confidence: 82%

Crystal and NMR Structures of a Peptidomimetic β‐Turn That Provides Facile Synthesis of 13‐Membered Cyclic Tetrapeptides

Cameron

Squire

Edwards

et al. 2017

Chemistry An Asian Journal

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“…Yudin and co-workers developed several elegant methods for site-specific incorporation of amino acids [50], peptide sequencing [51] and conformational control [52] of cyclic peptides based on the twisted amide electrophilic sites (Figure 24). In their approach, the integration of a highly strained and N -pyramidalized aziridinyl ring allows for selective N–C(O) cleavage and amino acid incorporation, while the strained aziridinyl ring provides a handle for further functionalization by aziridine-ring opening with nucleophiles.…”

Section: Miscellaneous Examplesmentioning

confidence: 99%

Chemistry of Bridged Lactams: Recent Developments

Szostak

2019

Molecules

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Bridged lactams represent the most effective and wide-ranging method of constraining the amide bond in a non-planar conformation. A previous comprehensive review on this topic was published in 2013 (Chem. Rev. 2013, 113, 5701–5765). In the present review, which is published as a part of the Special Issue on Amide Bond Activation, we present an overview of the recent developments in the field of bridged lactams that have taken place in the last five years and present a critical assessment of the current status of bridged lactams in synthetic and physical organic chemistry. This review covers the period from 2014 until the end of 2018 and is intended as an update to Chem. Rev. 2013, 113, 5701–5765. In addition to bridged lactams, the review covers recent advances in the chemistry of bridged sultams, bridged enamines and related non-planar structures.

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“…The conformational strain tolerated by therapeutically-relevant macrocyclic peptides upon target protein binding is postulated to be two to three times higher than that of small molecule ligands discussed above (Brueckner, unpublished). Apart from stapled peptides with rigid structures mimicking the protein-protein interaction (Phillips 2011), it is believed that a typical macrocyclic peptide will access complex conformational space in solution and adopt a significantly different conformation in the bound state (Goldbach 2019; Wahyudi et al 2014;Kranz 2006;Horne et al 2009;Chung et al 2016;Nikiforovich et al 2000;Cicero et al 1995). In a study that jointly utilized NMR, crystallographic and computational approaches, the importance of conformational dynamics for understanding and optimizing binding to the target protein is exhibited.…”

Section: Dynamics and Conformational Exchange Of Cyclic Peptides As Ligands In The Context Of Drug Designmentioning

confidence: 99%

The role of NMR in leveraging dynamics and entropy in drug design

et al. 2020

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Nuclear magnetic resonance (NMR) spectroscopy has contributed to structure-based drug development (SBDD) in a unique way compared to the other biophysical methods. The potency of a ligand binding to a protein is dictated by the binding free energy, which is an intricate interplay between entropy and enthalpy. In addition to providing the atomic resolution structural information, NMR can help to identify protein-ligand interactions that potentially contribute to the enthalpic component of the free energy. NMR can also illuminate dynamic aspects of the interaction, which correspond to the entropic term of the free energy. The ability of NMR to access both terms in the free energy equation stems from the suite of experiments developed to shed light on various aspects that contribute to both entropy and enthalpy, deepening our understanding of the biological function of macromolecules and assisting to target them in physiological conditions. Here we provide a brief account of the contribution of NMR to SBDD, highlighting hallmark examples and discussing the challenges that demand further method development. In the era of integrated biology, the unique ability of NMR to directly ascertain structural and dynamical aspects of macromolecule and monitor changes in these properties upon engaging a ligand can be combined with computational and other structural and biophysical methods to provide a more complete picture of the energetics of drug engagement with the target. Such efforts can be used to engineer better drugs.

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The reactivity and conformational control of cyclic tetrapeptides derived from aziridine-containing amino acids

Abstract: Regioselective ring-opening at a flexible N-acyl aziridine enables conformational control of α3β cyclic tetrapeptides through torsional strain.

Cited by 20 publications

References 52 publications

Crystal and NMR Structures of a Peptidomimetic β‐Turn That Provides Facile Synthesis of 13‐Membered Cyclic Tetrapeptides

Crystal and NMR Structures of a Peptidomimetic β‐Turn That Provides Facile Synthesis of 13‐Membered Cyclic Tetrapeptides

Chemistry of Bridged Lactams: Recent Developments

The role of NMR in leveraging dynamics and entropy in drug design

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