The unique crystallographic signature of a β-turn mimic nucleated by N-methylated phenylalanine and Aib as corner residue: conformational and self-assembly studies

Konar, Anita Dutt

doi:10.1039/c3ce41448e

Cited by 14 publications

(3 citation statements)

References 59 publications

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“…This assembled material was found to display high performances as catalyst in reduction reactions. Several other studies also reported the fabrication of ribbon and elongated fibrillar morphologies by short synthetic helical peptides [ 52 - 54 ].…”

Section: Nanostructures Of Helical Peptides For Diverse Functional Apmentioning

confidence: 99%

Self-assembly of Functional Nanostructures by Short Helical Peptide Building Blocks

Bera

Gazit

2019

PPL

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The self-assembly of short peptide building blocks into well-ordered nanostructures is a key direction in bionanotechnology. The formation of β -sheet organizations by short peptides is well explored, leading to the development of a wide range of functional assemblies. Likewise, many natural proteinaceous materials, such as silk and amyloid fibrils, are based on β-sheet structures. In contrast, collagen, the most abundant protein in mammals, is based on helical arrangement. Similar to β-sheet structures, short helical peptides have been recently discovered to possess a diverse set of functionalities with the potential to fabricate artificial self-assembling materials. Here, we outline the functional roles of self-assembled nanostructures formed by short helical peptides and their potential as artificial materials. We focus on the association between self-assembled mesoscale structures and their material function and demonstrate the way by which this class of building blocks bears the potential for diverse applications, such as the future fabrication of smart devices.

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Section: Nanostructures Of Helical Peptides For Diverse Functional Apmentioning

confidence: 99%

Self-assembly of Functional Nanostructures by Short Helical Peptide Building Blocks

Bera

Gazit

2019

PPL

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“…These two matriptase-selective compounds harbor similar P2 side chains, with disubstituted alpha carbons ( MD18 : Aib, MD24 : Acpc), which are the only representatives of this type of modification in our library. These alpha-disubstituted amino acids are known to induce a β-turn in the peptide structure, and we hypothesize that this conformational change could potentially be exploited to create matriptase selectivity by destabilizing interactions within TMPRSS6. , It is also possible that the β-carbons in position P2 are strongly hindered by the S2 pocket.…”

Section: Resultsmentioning

confidence: 99%

“…These alphadisubstituted amino acids are known to induce a β-turn in the peptide structure, and we hypothesize that this conformational change could potentially be exploited to create matriptase selectivity by destabilizing interactions within TMPRSS6. 42,43 It is also possible that the β-carbons in position P2 are strongly hindered by the S2 pocket.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Rational In Silico Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket

Desgagné,

Désilets,

Ferková

et al. 2024

J. Med. Chem.

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TMPRSS6 is a potential therapeutic target for the treatment of iron overload due to its role in regulating levels of hepcidin. Although potent TMPRSS6 inhibitors have been previously developed, their lack of specificity requires optimization to avoid potential side effects before pursuing preclinical development with in vivo models. Here, using computer-aided drug design based on a TMPRSS6 homology model, we reveal that the S2 position of TMPRSS6 offers a potential avenue to achieve selectivity against other members of the TTSP family. Accordingly, we synthesized novel peptidomimetic molecules containing lipophilic amino acids at the P2 position to exploit this unexplored pocket. This enabled us to identify TMPRSS6-selective small molecules with low nanomolar affinity. Finally, pharmacokinetic parameters were determined, and a compound was found to be potent in cellulo toward its primary target while retaining TTSPsubtype selectivity and showing no signs of alteration in in vitro TEER experiments.

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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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The unique crystallographic signature of a β-turn mimic nucleated by N-methylated phenylalanine and Aib as corner residue: conformational and self-assembly studies

Cited by 14 publications

References 59 publications

Self-assembly of Functional Nanostructures by Short Helical Peptide Building Blocks

Self-assembly of Functional Nanostructures by Short Helical Peptide Building Blocks

Rational In Silico Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket

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

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