925916-73-0Relevant articles and documents
Oligo(N-methylalanine) as a Peptide-Based Molecular Scaffold with a Minimal Structure and High Density of Functionalizable Sites
Fukuda, Yasuhiro,Kuroda, Daisuke,Morimoto, Jumpei,Sando, Shinsuke,Shiratori, Yota,Takeuchi, Koh,Tsumoto, Kouhei,Ueda, Takumi,Yokomine, Marin
supporting information, (2022/02/17)
Functionalizable synthetic molecules with nanometer sizes and defined shapes in water are useful as molecular scaffolds to mimic the functions of biomacromolecules and develop chemical tools for manipulating biomacromolecules. Herein, we propose oligo(N-methylalanine) (oligo-NMA) as a peptide-based molecular scaffold with a minimal structure and a high density of functionalizable sites. Oligo-NMA forms a defined shape in water without hydrogen-bonding networks or ring constraints, which enables the molecule to act as a scaffold with minimal atomic composition. Furthermore, functional groups can be readily introduced on the nitrogens and α-carbons of oligo-NMA. Computational and NMR spectroscopic analysis suggested that the backbone structure of oligo-NMA is not largely affected by functionalization. Moreover, the usefulness of oligo-NMA was demonstrated by the design of protein ligands. The ease of synthesis, minimal structure, and high functionalization flexibility makes oligo-NMA a useful scaffold for chemical and biological applications.
Tuning the Biological Activity of RGD Peptides with Halotryptophans ?
Kemker, Isabell,Schr?der, David C.,Feiner, Rebecca C.,Müller, Kristian M.,Marion, Antoine,Sewald, Norbert
, p. 586 - 601 (2021/01/14)
An array of l- and d-halotryptophans with different substituents at the indole moiety was synthesized employing either enzymatic halogenation by halogenases or incorporation of haloindoles using tryptophan synthase. Introduction of these Trp derivatives into RGD peptides as a benchmark system was performed to investigate their influence on bioactivity. Halotryptophan-containing RGD peptides display increased affinity toward integrin αvβ3 and enhanced selectivity over integrin α5β1. In addition, bromotryptophan was exploited as a platform for late-stage diversification by Suzuki-Miyaura cross-coupling (SMC), resulting in new-to-nature biaryl motifs. These peptides show enhanced affinity toward αvβ3, good affinity to αvβ8, and remarkable selectivity over α5β1 and αIIbβ3 while featuring fluorogenic properties. Their feasibility as a probe was demonstrated in vitro. Extensive molecular dynamics simulations were undertaken to elucidate NMR and high-performance liquid chromatography (HPLC) data for these late-stage diversified cyclic RGD peptides and to further characterize their conformational preferences.
Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure ?
Martin, Charlotte,Gimenez, Luis E.,Williams, Savannah Y.,Jing, Yu,Wu, Yiran,Hollanders, Charlie,Van Der Poorten, Olivier,Gonzalez, Simon,Van Holsbeeck, Kevin,Previti, Santo,Lamouroux, Arthur,Zhao, Suwen,Tourwé, Dirk,Stevens, Raymond C.,Cone, Roger D.,Ballet, Steven
supporting information, p. 357 - 369 (2020/12/01)
The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist SHU-9119 (Ac-Nle4-c[Asp5-His6-DNal(2′)7-Arg8-Trp9-Lys10]-NH2). These analogues were pharmacologically characterized in vitro, giving key insights into exploiting binding site subpockets to deliver more selective ligands. More specifically, the side chains of the Nle4, DNal(2′)7, and Trp9 residues in SHU-9119, as well as the amide linkage between the Asp5 and Lys10 side chains, were found to represent structural features engaging a hMC4R/hMC3R selectivity switch.
PEPTIDOMIMETIC MACROCYCLES AND USES THEREOF
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Paragraph 0448; 0455, (2020/02/17)
The present disclosure describes the synthesis of peptidomimetic macrocycles and methods of using peptidomimetic macrocycles to treat a condition. The present disclosure also describes methods of using peptidomimetic macrocycles in combination with at least one additional pharmaceutically-active agent for the treatment of a condition, for example, cancer.
PEPTIDOMIMETIC MACROCYCLES AND USES THEREOF
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Paragraph 0371; 0377, (2020/10/09)
The present disclosure describes methods of using peptidomimetic macrocycles in combination with an additional therapy to treat a condition, for example, cancer. In some embodiments, the peptidomimetic macrocycle can mitigate a side effect (e.g., mucositis, neutropenia, or thrombocytopenia) of the additional therapy.
MACROCYCLIC PEPTIDOMIMETICS FOR ALPHA-HELIX MIMICRY
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, (2015/11/02)
Methods and compositions are provided for generating macrocyclic peptides constrained by side-chain-to-C-terminus non-peptidic tethers for use as functional and structural mimics of α-helical motifs, including in therapeutic applications. These methods can be used to produce libraries of conformationally constrained peptidomimetics to identify compounds with desired activity properties.
Synthesis of cell-permeable stapled peptide dual inhibitors of the p53-Mdm2/Mdmx interactions via photoinduced cycloaddition
Madden, Michael M.,Muppidi, Avinash,Li, Zhenyu,Li, Xiaolong,Chen, Jiandong,Lin, Qing
supporting information; experimental part, p. 1472 - 1475 (2011/04/23)
We report the first application of a photoinduced 1,3-dipolar cycloaddition reaction to 'staple' a peptide dual inhibitor of the p53-Mdm2/Mdmx interactions. A series of stapled peptide inhibitors were efficiently synthesized and showed excellent dual inhi
β-Peptides with improved affinity for hDM2 and hDMX
Harker, Elizabeth A.,Daniels, Douglas S.,Guarracino, Danielle A.,Schepartz, Alanna
experimental part, p. 2038 - 2046 (2009/06/06)
We previously described a series of 314-helical β-peptides that bind the hDM2 protein and inhibit its interaction with a p53-derived peptide in vitro. Here we present a detailed characterization of the interaction of these peptides with hDM2 an
