Article
Chemistry, Organic
Melanie Trobe, Martin Vareka, Till Schreiner, Patrick Dobrounig, Carina Doler, Ella B. Holzinger, Andreas Steinegger, Rolf Breinbauer
Summary: Teraryl-based alpha-helix mimetics have been synthesized using a modular and flexible approach in order to inhibit protein-protein interactions (PPI). The synthesis method involves the use of a benzene core unit with two leaving groups of differentiated reactivity in Pd-catalyzed cross-coupling for teraryl assembly. Core fragments corresponding to previously missing amino acids have been reported, completing the set of relevant amino acid analogues.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Melanie Trobe, Julia Blesl, Martin Vareka, Till Schreiner, Rolf Breinbauer
Summary: Teraryl-based alpha-helix mimetics have been synthesized using a modular and flexible approach, where a benzene core unit with two halide leaving groups of differentiated reactivity was used. The issue of hydrolysis during cross-coupling was resolved by using para-bromo iodoarene core fragments. A complete set of para-bromoiodoarene core fragments decorated with side chains of all relevant amino acids for PPI was reported. Some of the nucleophilic side chains were provided in a protected form to be compatible with general cross-coupling conditions.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Melanie Trobe, Till Schreiner, Martin Vareka, Sebastian Grimm, Bernhard Woelfl, Rolf Breinbauer
Summary: This study presents a method for synthesizing teraryl-based alpha-helix mimetics and enhancing their water solubility using pyridine-containing boronic acid building blocks. The researchers have successfully synthesized pyridine-based boronic acid building blocks decorated with amino acid side chains relevant to protein-protein interactions. The study also reveals the influence of pyridine rings on the solubility of teraryls.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Lara E. Zetzsche, Jessica A. Yazarians, Suman Chakrabarty, Meagan E. Hinze, Lauren A. M. Murray, April L. Lukowski, Leo A. Joyce, Alison R. H. Narayan
Summary: This study demonstrates the use of cytochrome P450 enzymes for biocatalytic cross-coupling reactions, enabling the formation of sterically hindered biaryl bonds through oxidative C-C bond formation. By engineering the substrate and atroposelectivity of the P450 enzyme, a highly efficient and selective process has been developed.
Article
Genetics & Heredity
Li-Ping Li, Bo Zhang, Li Cheng
Summary: Identification and characterization of plant protein-protein interactions (PPIs) are crucial in understanding protein functions and molecular mechanisms in plant cells. This article proposes a computational framework, CPIELA, for predicting plant PPIs, which combines PSSM, LOOP, and ROF model. Experimental results demonstrate that CPIELA achieved high prediction accuracies and outperforms other state-of-the-art methods. CPIELA has the potential to be a useful tool in identifying possible plant PPIs.
FRONTIERS IN GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Kazuya Kobayashi, Takuya Otani, Saki Ijiri, Yuki Kawasaki, Hiroki Matsubara, Takahiro Miyagi, Taishi Kitajima, Risa Iseki, Katsuyasu Ishizawa, Naoka Shindo, Kouta Okawa, Kouta Ueda, Syun Ando, Momoka Kawakita, Yasunao Hattori, Kenichi Akaji
Summary: The introduction of an aromatic substituent into a HEA-type BACE1 inhibitor enhanced inhibitory activity, with the R-configuration improving activity and methyl substitution decreasing activity. Isosteres with different hydroxyl and methyl configurations were prepared using a branched synthesis approach, and the effect on inhibitory activity was evaluated. Derivatives with various substituents at the P1' site showed clear effects on BACE1 activity, leading to the identification of a highly potent inhibitor.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Organic
Ivan Keng Wee On, Wenyang Hong, Ye Zhu
Summary: Enzymes utilize non-covalent interactions to achieve precise site-selectivity and stereoselectivity in transformations. This study demonstrates the use of a chiral ionic ligand to facilitate remote selectivity and enantioselectivity through electrostatic steering, enabling an ionic-directed remote meta-selective atroposelective Suzuki-Miyaura coupling.
TETRAHEDRON LETTERS
(2023)
Article
Biotechnology & Applied Microbiology
Kolja Stahl, Andrea Graziadei, Therese Dau, Oliver Brock, Juri Rappsilber
Summary: Limitations of Alphafold2 structure prediction are overcome by incorporating experimentally determined distance constraints using AlphaLink. This modified version improves prediction for challenging targets by utilizing sparse experimental contacts and can predict distinct protein conformations. Experimental data on residue-residue contacts obtained through crosslinking mass spectrometry validates the improved performance. The noise-tolerant framework for integrating data allows accurate characterization of protein structures from in-cell data.
NATURE BIOTECHNOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Jie Xu, Samantha Grosslight, Kyle A. Mack, Sierra C. Nguyen, Kyle Clagg, Ngiap-Kie Lim, Jacob C. Timmerman, Jeff Shen, Nicholas A. White, Lauren E. Sirois, Chong Han, Haiming Zhang, Matthew S. Sigman, Francis Gosselin
Summary: An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036, was reported. The synthesis involved a highly selective Negishi coupling and a series of reaction sequences, leading to the desired compound with a 40% overall yield from the starting materials.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Sin Hang Crystal Chan, Jarred M. Griffin, Connor A. Clemett, Margaret A. Brimble, Simon J. O'Carroll, Paul W. R. Harris
Summary: Peptide5 is a mimetic peptide with 12 amino acids that plays an important role in cell-to-cell communication. In order to improve its activity and stability, twenty-five novel mimetics were designed and synthesized. The results showed that one variant, H-VDCFLSRPTE-N-MeKT-OH, exhibited good activity and stability.
FRONTIERS IN CHEMISTRY
(2022)
Article
Chemistry, Physical
Sanita B. Tailor, Mattia Manzotti, Gavin J. Smith, Sean A. Davis, Robin B. Bedford
Summary: The cobalt-catalyzed Suzuki biaryl cross-coupling reaction using alkoxide bases, with strict stoichiometric control and selection of the right boron ester, is shown to be achievable. Excessive alkoxide bases or lithium additives can inhibit or poison the catalyst, while a neopentane diol-based boron ester is crucial for optimal performance.Mechanistic and computational studies have been carried out to investigate the reaction mechanism and explain unexpected observations.
Article
Chemistry, Physical
Wendi Luo, Xiaocui Fang, Chen Wang, Yanlian Yang, Bin Tu, Qiaojun Fang
Summary: Peptide-modified delivery systems have great potential in improving targeting specificity, biocompatibility, and stability. However, designing a peptide-decorated surface with specific function remains challenging due to a lack of understanding of the interactions between surface-bound peptide ligands and their receptors.
Article
Biochemistry & Molecular Biology
Ryan A. Dohoney, Johnson A. Joseph, Charles Baysah, Alexandra G. Thomas, Apshara Siwakoti, Tyler D. Ball, Sunil Kumar
Summary: Abberent protein-protein interactions (aPPIs) play a crucial role in pathological conditions and can be targeted for therapeutic purposes. We have developed a chromatography-free method to synthesize a highly diverse chemical library of oligopyridylamides (OPs) to enhance affinity for disease-relevant targets.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Organic
Yuichiro Kawamoto, Toyoharu Kobayashi, Hisanaka Ito
Summary: Stachyodin A, with a unique spirotetrahydrofuran ring system, was isolated from the roots of Indigofera stachyodes in 2018. The first total synthesis of racemic stachyodin A was accomplished in 14 steps.
Article
Chemistry, Physical
Paul O. Peterson, Matthew Joannou, Eric M. Simmons, Steven R. Wisniewski, Junho Kim, Paul J. Chirik
Summary: The synthesis and characterization of phenoxy(imine) iron(II) alkyl precatalysts for C(sp2)-C(sp3) Suzuki-Miyaura cross-coupling reaction is reported. This method utilizes mild alkoxide bases and nonpolar solvents to achieve high efficiency C(sp2)-C(sp3) bond formation with various aryl boronic esters and alkyl bromides. The study also highlights the compatibility of the precatalysts with base-sensitive functionality and the role of boronate intermediates in transmetalation.
Review
Biochemistry & Molecular Biology
Rita Fuerst, Rolf Breinbauer
Summary: ABPP has been widely used for measuring protein activity, annotating unknown protein functions, and studying small-molecule inhibitor targets. Oxidoreductases have received less attention in ABPP, with probes developed for oxidases but none for reductases, presenting opportunities for future research.
Article
Cardiac & Cardiovascular Systems
Arne Thiele, Katja Luettges, Daniel Ritter, Niklas Beyhoff, Elia Smeir, Jana Grune, Julia S. Steinhoff, Michael Schupp, Robert Klopfleisch, Michael Rothe, Nicola Wilck, Hendrik Bartolomaeus, Anna K. Migglautsch, Rolf Breinbauer, Erin E. Kershaw, Gernot F. Grabner, Rudolf Zechner, Ulrich Kintscher, Anna Foryst-Ludwig
Summary: The specific inhibitor of ATGL, Atglistatin, can alleviate catecholamine-induced cardiac damage by exerting anti-fibrotic and anti-apoptotic effects. These effects are likely mediated by non-cardiac tissues.
CARDIOVASCULAR RESEARCH
(2022)
Article
Chemistry, Organic
Melanie Trobe, Till Schreiner, Martin Vareka, Sebastian Grimm, Bernhard Woelfl, Rolf Breinbauer
Summary: This study presents a method for synthesizing teraryl-based alpha-helix mimetics and enhancing their water solubility using pyridine-containing boronic acid building blocks. The researchers have successfully synthesized pyridine-based boronic acid building blocks decorated with amino acid side chains relevant to protein-protein interactions. The study also reveals the influence of pyridine rings on the solubility of teraryls.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Melanie Trobe, Julia Blesl, Martin Vareka, Till Schreiner, Rolf Breinbauer
Summary: Teraryl-based alpha-helix mimetics have been synthesized using a modular and flexible approach, where a benzene core unit with two halide leaving groups of differentiated reactivity was used. The issue of hydrolysis during cross-coupling was resolved by using para-bromo iodoarene core fragments. A complete set of para-bromoiodoarene core fragments decorated with side chains of all relevant amino acids for PPI was reported. Some of the nucleophilic side chains were provided in a protected form to be compatible with general cross-coupling conditions.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Melanie Trobe, Martin Vareka, Till Schreiner, Patrick Dobrounig, Carina Doler, Ella B. Holzinger, Andreas Steinegger, Rolf Breinbauer
Summary: Teraryl-based alpha-helix mimetics have been synthesized using a modular and flexible approach in order to inhibit protein-protein interactions (PPI). The synthesis method involves the use of a benzene core unit with two leaving groups of differentiated reactivity in Pd-catalyzed cross-coupling for teraryl assembly. Core fragments corresponding to previously missing amino acids have been reported, completing the set of relevant amino acid analogues.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Gernot F. Grabner, Nikolaus Guttenberger, Nicole Mayer, Anna K. Migglautsch-Sulzer, Christian Lembacher-Fadum, Nermeen Fawzy, Dominik Bulfon, Peter Hofer, Thomas Zuellig, Lennart Hartig, Natalia Kulminskaya, Gabriel Chalhoub, Margarita Schratter, Franz P. W. Radner, Karina Preiss-Landl, Sarah Masser, Achim Lass, Rudolf Zechner, Karl Gruber, Monika Oberer, Rolf Breinbauer, Robert Zimmermann
Summary: This study reports the development and biological characterization of the first small-molecule inhibitor of human ATGL. This inhibitor selectively inactivates ATGL in humans and nonhuman primates, providing a potential therapeutic option for lipotoxicity-driven disorders.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Harald Podversnik, Shalinee Jha, Peter Macheroux, Rolf Breinbauer
Summary: DPP3 is a widely expressed enzyme involved in various physiological processes. We have designed peptide-based inhibitors to effectively inhibit the activity of DPP3.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Sabine Kienesberger, Amar Cosic, Maksym Kitsera, Sandra Raffl, Marlene Hiesinger, Eva Leitner, Bettina Halwachs, Gregor Gorkiewicz, Ronald A. Glabonjat, Georg Raber, Christian Lembacher-Fadum, Rolf Breinbauer, Stefan Schild, Ellen L. Zechner
Summary: The enterotoxin tilimycin produced by gut-resident Klebsiella species can alter gut microbiota composition, induce mutational evolution and drive the emergence of antibiotic resistance in mice. Tilimycin reduces the microbial richness in the gut, promotes mutations in opportunistic pathogens, and contributes to the development of antibiotic resistance.
NATURE MICROBIOLOGY
(2022)
Review
Chemistry, Multidisciplinary
Leo Krammer, Rolf Breinbauer
Summary: Activity-based protein profiling (ABPP) is a useful proteomic tool that measures the activity of enzymes or proteins in their cellular environment. It can annotate the function of uncharacterized proteins and investigate the target profile of small molecule inhibitors. However, ABPP of oxidoreductases has received less attention compared to other enzyme classes.
ISRAEL JOURNAL OF CHEMISTRY
(2023)
Article
Biotechnology & Applied Microbiology
Tuo Li, Annika J. E. Borg, Leo Krammer, Rolf Breinbauer, Bernd Nidetzky
Summary: This study demonstrates a biocatalytic process for the reaction-intensified production of di-C-beta-glucosides from sucrose, which are rare natural plant products with unique properties. The synthesis proceeds through an iterative two-fold C-glycosylation reaction catalyzed by a kumquat di-C-glycosyltransferase and uses UDP-Glc provided by a soybean sucrose synthase. The di-C-glycosylation is driven to completion with a constant supply of UDP-Glc, resulting in high yields of di-C-glucosides.
BIOTECHNOLOGY AND BIOENGINEERING
(2023)
Article
Biochemistry & Molecular Biology
Julia Kriegesmann, Thomas Schlatzer, Kateryna Che, Claudia Altdorf, Susanne Huhmann, Hanspeter Kaehlig, Dennis Kurzbach, Rolf Breinbauer, Christian F. W. Becker
Summary: We demonstrated the extension of chemoselective Pd-catalyzed cysteine allylation reaction to stapling and the subsequent modification of alkene-containing staples to introduce additional probes into stabilized peptides. The introduction of fluorophore and PEG moieties into stapled peptides was achieved using bioorthogonal thiol-ene and Diels-Alder reactions. The structural implications of allyl staples, when used to replace conformationally relevant disulfide bridges, were investigated in a selective integrin alpha(3)beta(1) binder (LXY3) to enhance stability and binding affinity.
Article
Cell Biology
Lisa Poltl, Maksym Kitsera, Sandra Raffl, Stefan Schild, Amar Cosic, Sabine Kienesberger, Katrin Unterhauser, Georg Raber, Christian Lembacher-Fadum, Rolf Breinbauer, Gregor Gorkiewicz, Carlos Sebastian, Gerald Hoefler, Ellen L. Zechner
Summary: The DNA-alkylating metabolite tilimycin is a microbial genotoxin that causes colitis in individuals carrying til+ Klebsiella spp. Intestinal stem cells are affected by tilimycin-induced DNA damage, leading to genetic aberrations and increased disease susceptibility in the colon. The presence of tilimycin-producing Klebsiella results in higher frequencies and more mutations per individual compared to non-producing mutants.
Article
Immunology
Elien Grajchen, Melanie Loix, Paulien Baeten, Beatriz F. Corte-Real, Ibrahim Hamad, Sam Vanherle, Mansour Haidar, Jonas Dehairs, Jelle Y. Broos, James M. Ntambi, Robert Zimmermann, Rolf Breinbauer, Piet Stinissen, Niels Hellings, Sanne G. S. Verberk, Gijs Kooij, Martin Giera, Johannes V. Swinnen, Bieke Broux, Markus Kleinewietfeld, Jerome J. A. Hendriks, Jeroen F. J. Bogie
Summary: The imbalance between pathogenic and protective T cell subsets is a key feature of autoimmune disorders such as multiple sclerosis (MS). The molecular mechanisms underlying the impact of fatty acid metabolism on T cell physiology and autoimmunity are poorly understood. The study reveals that fatty acid desaturation by SCD1 acts as an endogenous brake on regulatory T-cell differentiation and enhances autoimmunity, suggesting potential therapeutic strategies for autoimmune disorders such as MS.
CELLULAR & MOLECULAR IMMUNOLOGY
(2023)
Review
Chemistry, Applied
Maria Degli Innocenti, Till Schreiner, Rolf Breinbauer
ADVANCED SYNTHESIS & CATALYSIS
(2023)
Meeting Abstract
Cardiac & Cardiovascular Systems
Max Stahnke, Juliane Schwanbeck, Madeleine Goeritzer, Dagmar Kolb, Gernot F. Grabner, Rolf Breinbauer, Rudolf Zechner, Anna Foryst-Ludwig, Ulrich Kintscher
