112257-19-9Relevant articles and documents
Chemical Synthesis of Native S-Palmitoylated Membrane Proteins through Removable-Backbone-Modification-Assisted Ser/Thr Ligation
Barbot, Thomas,Beswick, Veronica,Cao, Xiu-Xiu,Huang, Dong-Liang,Jamin, Nadège,Jaxel, Christine,Li, Ying,Liang, Jun,Montigny, Cédric,Tian, Chang-Lin,Xue, Min,Zheng, Ji-Shen,Zheng, Yong
, p. 5178 - 5184 (2020)
The preparation of native S-palmitoylated (S-palm) membrane proteins is one of the unsolved challenges in chemical protein synthesis. Herein, we report the first chemical synthesis of S-palm membrane proteins by removable-backbone-modification-assisted Ser/Thr ligation (RBMGABA-assisted STL). This method involves two critical steps: 1) synthesis of S-palm peptides by a new γ-aminobutyric acid based RBM (RBMGABA) strategy, and 2) ligation of the S-palm RBM-modified peptides to give the desired S-palm product by the STL method. The utility of the RBMGABA-assisted STL method was demonstrated by the synthesis of rabbit S-palm sarcolipin (SLN) and S-palm matrix-2 (M2) ion channel. The synthesis of S-palm membrane proteins highlights the importance of developing non-NCL methods for chemical protein synthesis.
An efficient methodology to introduce o-(aminomethyl)phenyl-boronic acids into peptides: alkylation of secondary amines
Hernandez, Erik T.,Kolesnichenko, Igor V.,Reuther, James F.,Anslyn, Eric V.
, p. 126 - 133 (2016)
Current approaches for incorporating boronic acids into peptides require one of the following: the synthesis of commercially unavailable pinacol-protected boronate ester amino acid building blocks, amidation of small-molecule amine-containing boronic acids, or reductive amination of amine residues with 2-formylphenyl boronic acid. These methods have drawbacks, such as the use of excess starting materials, the lack of reactive-site specificity, or the inability to add multiple boronic acids in solution. In addition, several of these approaches do not allow for incorporation of the critical o-aminomethyl functionality that allows for binding of saccharides under physiological conditions. In this work, we report three methods to functionalize synthetic peptides with boronic acids using solid-phase and solution-phase chemistries by alkylating a secondary amine with o-(bromomethyl)phenylboronic acid. Solution-phase chemistries afforded the highest yields, and were used to synthesize seven complex biotinylated multi-boronic acid peptides.
Amplified Self-Immolative Release of Small Molecules by Spatial Isolation of Reactive Groups on DNA-Minimal Architectures
Hennecker, Christopher,Mittermaier, Anthony,Prinzen, Alexander L.,Saliba, Daniel,Sleiman, Hanadi F.,Trinh, Tuan
, p. 12900 - 12908 (2020)
Triggering the release of small molecules in response to unique biomarkers is important for applications in drug delivery and biodetection. Due to low quantities of biomarker, amplifying release is necessary to gain appreciable responses. Nucleic acids have been used for both their biomarker-recognition properties and as stimuli, notably in amplified small-molecule release by nucleic-acid-templated catalysis (NATC). The multiple components and reversibility of NATC, however, make it difficult to apply in vivo. Herein, we report the use of the hybridization chain reaction (HCR) for the amplified, conditional release of small molecules from standalone nanodevices. We couple HCR with a DNA-templated reaction resulting in the amplified, immolative release of small molecules. We integrate the HCR components into single nanodevices as DNA tracks and spherical nucleic acids, spatially isolating reactive groups until triggering. This could be applied to biosensing, imaging, and drug delivery.
New contributions to the drug profile of TNFα inhibitor SPD304: Affinity, selectivity and ADMET considerations
Mascret, A?da,Mouhsine, Hadley,Attia, Ghada,Cabrera, Damien,Benchekroun, Mohamed,Gizzi, Patrick,Zerrouki, Chouki,Fourati, Najla,Zagury, Jean-Fran?ois,Veitía, Maité Sylla-Iyarreta,Port, Marc
supporting information, (2021/07/13)
Tumor necrosis factor alpha (TNFα) is a relevant clinical target for the treatment of chronic inflammatory diseases. Currently, only few small molecules are known as direct inhibitors of TNFα. To date, none of these molecules has shown both an efficient a
Selective Covalent Targeting of Mutated EGFR(T790M) with Chlorofluoroacetamide-Pyrimidines
Fuchida, Hirokazu,Hosokawa, Keitaro,Inamori, Ryo,Koyanagi, Satoru,Kuwata, Keiko,Matsunaga, Naoya,Ohdo, Shigehiro,Ojida, Akio,Ono, Mayumi,Sato, Mami,Shibata, Tomohiro,Shindo, Naoya,Tokunaga, Keisuke,Watari, Kosuke,Xiao-Lin, Guo
supporting information, p. 1137 - 1144 (2020/07/04)
Covalent modification of disease-associated proteins with small molecules is a powerful approach for achieving an increased and sustained pharmacological effect. To reduce the potential risk of nonselective covalent modification, molecular design of covalent inhibitors is critically important. We report herein the development of a targeted covalent inhibitor for mutated epidermal growth factor receptor (EGFR) (L858R/T790M) using α-chlorofluoroacetamide (CFA) as the reactive group. The chemically tuned weak reactivity of CFA was suitable for the design of third-generation EGFR inhibitors that possess the pyrimidine scaffold. The structure-activity relationship study revealed that CFA inhibitor 18 (NSP-037) possessed higher inhibition selectivity to the mutated EGFR over wild-type EGFR when compared to clinically approved osimertinib. Mass-based chemical proteomics analyses further revealed that 18 displayed high covalent modification selectivity for the mutated EGFR in living cells. These findings highlight the utility of CFA as a warhead of targeted covalent inhibitors and the potential application of the CFA-pyrimidines for treatment of non-small-cell lung cancer.
