Improved deconvolution of natural products’ protein targets using diagnostic ions from chemical proteomics linkers

• Andreas Wiest and
• Pavel Kielkowski

Beilstein J. Org. Chem. 2024, 20, 2323–2341, doi:10.3762/bjoc.20.199

• ][36][37]. A covalent bond between a probe and a protein is needed because of denaturing conditions used during the analysis. In contrast, relying on a noncovalent interaction would result in loss of the probe–protein interaction. The bioorthogonal handle is therefore essential for an enrichment or

• probe–protein interaction in native conditions in living cells. Taken together, the linkers used in chemical proteomics workflows are applied broadly in many research areas including screening of fragment libraries, covalent modifiers, protein PTMs, protein–protein interactions, protein–nucleic acid

• gel and subjected to MS analysis to identify the labeled proteins [77][78]. The in-gel analysis is often used for target validation with corresponding protein mutants or knockout cell lines, with loss of the identified probe–protein interaction leading to disappearance of the fluorescence band from

Computational toolbox for the analysis of protein–glycan interactions

• Ferran Nieto-Fabregat,
• Maria Pia Lenza,
• Angela Marseglia,
• Cristina Di Carluccio,
• Antonio Molinaro,
• Alba Silipo and
• Roberta Marchetti

Beilstein J. Org. Chem. 2024, 20, 2084–2107, doi:10.3762/bjoc.20.180

• computational tools have been developed to facilitate the prediction of protein binding sites. We report here only the applications related to the protein interaction with glycans: 1. PeSTo-Carbs [105]: it is an extension of Protein Structure Transformer (PeSTo) [106], a deep learning method to predict protein

• interaction interfaces with other proteins, nucleic acids, lipids, small molecules, and ions, starting from a protein structure. PeSTo-Carbs is specifically trained to predict carbohydrate and cyclodextrin binding interfaces on proteins. Two different modules are available: a general model PS-G for a wide

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Identification of the p-coumaric acid biosynthetic gene cluster in Kutzneria albida: insights into the diazotization-dependent deamination pathway

• Seiji Kawai,
• Akito Yamada,
• Yohei Katsuyama and
• Yasuo Ohnishi

Beilstein J. Org. Chem. 2024, 20, 1–11, doi:10.3762/bjoc.20.1

• protein–protein interaction between the carrier protein and AMP-dependent ligase and (ii) the chain length control of highly reducing type II PKSs. Experimental Strains, chemicals, and enzymes E. coli JM109 was used for DNA manipulation, and E. coli BL21(DE3) was used for expressing recombinant proteins

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• needs a covalent bond between the two domains A and B, as indicated by a similar precipitation of domain B alone and domain B in the presence of domain A. In these experiments, the N-terminal His-tags at both domains A and B may influence protein–protein interaction with the consequence that the mixture

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• against human myeloid leukemia cells, and stabilizes the 14-3-3 – TASK3 protein–protein interaction [29][30]. Sugita et al. investigated the synthesis of the core structure of cotylenol (50) first through an RCM approach on the advanced intermediate 47 (Scheme 7) [31]. Despite many attempts, the authors

Microelectrode arrays, electrosynthesis, and the optimization of signaling on an inert, stable surface

• Kendra Drayton-White,
• Siyue Liu,
• Yu-Chia Chang,
• Sakashi Uppal and
• Kevin D. Moeller

Beilstein J. Org. Chem. 2022, 18, 1488–1498, doi:10.3762/bjoc.18.156

• than enough electrodes in any one region of the array for an extensive study. With that information in place, attention was turned back to the initial small molecule/G-protein interaction that lies at the heart of guiding the synthetic study proposed in connection with Figure 1. Initially, the same

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1070–1078, doi:10.3762/bjoc.18.109

• receptors 1 [3], AChE and BACE-1 inhibitor 2 [4], inhibitor of oncogenic p53-MDM2 protein–protein interaction 3 [5], positive allosteric modulator of ionotropic glutamate receptor NMDA-1 4 [6], insulin-like growth factor 1 receptor inhibitor 5 [7], and metabotropic glutamate receptor 7 modulator 6 [8

Molecular basis for protein–protein interactions

• Brandon Charles Seychell and
• Tobias Beck

Beilstein J. Org. Chem. 2021, 17, 1–10, doi:10.3762/bjoc.17.1

• ], producing two different modes of binding: pH-dependent and salt-dependent binding mechanisms. In a pH-dependent binding mechanism, an overall proton is either released or taken up during the protein interaction due to the binding-induced pKa shift of acidic or basic amino acids present at the complex

Leveraging glycomics data in glycoprotein 3D structure validation with Privateer

• Haroldas Bagdonas,
• Daniel Ungar and
• Jon Agirre

Beilstein J. Org. Chem. 2020, 16, 2523–2533, doi:10.3762/bjoc.16.204

• /glycoproteomics to carbohydrate 3D model building and validation in Privateer Many fields, for example pharmaceutical design and engineering [58], molecular dynamics simulations [59] and protein interaction studies [60], rely upon structural biology to produce accurate atomistic descriptions of glycoproteins

NMR Spectroscopy of supramolecular chemistry on protein surfaces

• Peter Bayer,
• Anja Matena and
• Christine Beuck

Beilstein J. Org. Chem. 2020, 16, 2505–2522, doi:10.3762/bjoc.16.203

• combination of two or more GCP moieties with variable linkers enables the construction of multivalent ligands geared towards a specific spot on protein surface, which by design can lead to either stabilization [42][43][44][45] or inhibition [46] of a given protein–protein interaction. The inhibition of the

• indeed recognize the highly positively charged area on cytochrome c (Cyt c) that binds Cyt c peroxidase. The inhibition of this protein–protein interaction was demonstrated as well using a luminescence quenching assay. The protein surface recognition of two porphyrin ligands bearing carboxylate

• perturbation and line broadening observed in the 1H,15N-HSQC titrations. The smallest ligand 4PSA showed the highest specificity, locating to the hydrophobic triad, where ubiquitin binds many of its protein interaction partners, which is surrounded by cationic residues. The flat, hydrophobic pyrene core can

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• Modares University, P.O. Box 14155-4838, Tehran, Iran Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland 10.3762/bjoc.15.45 Abstract Macrocycles were designed to antagonize the protein–protein interaction p53-MDM2 based on the three-finger pharmacophore F19W23L25. The

• MDM2–p53 interaction could enable p53 and reverse tumor formation [26][27][28]. Based on our knowledge to antagonize the oncogenic protein–protein interaction p53–MDM2 [23][29][30][31][32][33][34][35][36][37][38][39][40] we designed macrocyclic inhibitors in continuation of our previous work [13][23

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• vast majority of protein–protein interaction modulators execute their activity through inhibition, stabilization of specific protein complexes could also be therapeutically beneficial [23][24]. Even though historically PPIs have been considered to be “undruggable”, recent remarkable medicinal chemistry

• of rapamycin) [34]. This natural product, isolated from Streptomyces hygroscopicus, was one of the first protein–protein interaction stabilizers reported: it first binds to its receptor (i.e., FKBP12) with high affinity, after which the FKBP12-rapamycin complex will associate with TOR resulting in

• inhibition of the catalytic activity of the enzyme [23]. All these drug discovery successes have validated PPIs as a target and, in conjunction with the elucidation and reconstruction of protein–protein interaction networks in bacteria, have paved the way towards the development of novel and promising

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• grooves, but also by making close contacts with individual bases within the local helix architecture. Over the last four decades, much research has been reported on the development of small non-natural ligands as therapeutics to either block, or in some cases, mimic a DNA–protein interaction of interest

Fluorescent nucleobase analogues for base–base FRET in nucleic acids: synthesis, photophysics and applications

• Mattias Bood,
• Sangamesh Sarangamath,
• Moa S. Wranne,
• Morten Grøtli and
• L. Marcus Wilhelmsson

Beilstein J. Org. Chem. 2018, 14, 114–129, doi:10.3762/bjoc.14.7

• cellular processes without perturbing the system under study. In another report using the tCO–tCnitro FRET pair as a probe of protein interaction, Ansari et al. investigated the DNA damage repair system [82]. Here the FRET pair is used to better understand the conformational dynamics along the DNA-lesion

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• the biological activity obtained with synthetic molecules was fundamental for the understanding the structural basis of endotoxin-protein interaction. Preparation of Kdo-lipid A represents an even greater synthetic challenge than lipid A per se. The synthesis of E. coli type Kdo2-lipid A (Re-LPS) was

Glyco-gold nanoparticles: synthesis and applications

• Federica Compostella,
• Olimpia Pitirollo,
• Alessandro Silvestri and
• Laura Polito

Beilstein J. Org. Chem. 2017, 13, 1008–1021, doi:10.3762/bjoc.13.100

• spacer in the glycan–protein interaction [67]. The authors considered different types of spacer in terms of chemical structure, length and rigidity and demonstrated that longer linkers resulted as the best performing ones, giving a better access to the protein pocket. Furthermore, they showed that rigid

• efforts, the GAuNPs showed an incremented lectin identification power, at low protein concentrations, enabling an easy tool for sugar–lectin recognition. The glycan–protein interaction has been studied as well employing surface-enhanced Raman spectroscopy (SERS) exploiting AuNP ability in amplifying Raman

• relevance. Long et al. [50] developed a simple procedure to analyze in real-time the carbohydrate–protein interaction at the single NP level, using for the first time an unusual technique such as the dark field microscopy, DFM (Figure 3). Briefly, the method is based on the interaction among 60 nm AuNPs

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• a syringe through the cuvette filled with protein solution. Protein interaction studies The interaction analysis of StaF with the A47934 X-domain (Xsta) was done by analytical size-exclusion chromatography (SEC) using a Superose 12 10/300 GL column connected to an Äkta pure 25 system and the unicorn

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• biocompatible polymers, namely linear poly(N-2-hydroxypropyl)methacrylamide (pHPMA), hyperbranched polyglycerol (hPG), and linear 2-carboxyethyldextran are suited for the construction of peptide–polymer conjugates, which can be used as potent multivalent ligands for a flexible protein–protein interaction site

• crosslinking ligands for protein–protein interaction sites and whether the ligands active in the protein binding assay can be further developed toward intracellularly delivered and intracellularly active PPI-inhibitors of the tandem WW-domain. Comparing the entropy loss during ligand–receptor interactions in

Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW

• Lisa Maria Henning,
• Sumati Bhatia,
• Miriam Bertazzon,
• Michaela Marczynke,
• Oliver Seitz,
• Rudolf Volkmer,
• Rainer Haag and
• Christian Freund

Beilstein J. Org. Chem. 2015, 11, 701–706, doi:10.3762/bjoc.11.80

• release of the dendritic polymer into the cytoplasm [13]. These polymeric scaffolds have been explored well for tumor targeting by using polymer-drug conjugates or polyplexes with genes or siRNA [14], but also have the potential to inhibit protein–protein interaction in cells, by displaying multiple

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• -like structures and can be used for helical self-association towards protein-like assemblies mimicking secondary structures and eventually acting as inhibitors for protein–protein interaction [13][14]. In addition, β-peptide 314-helices furnish an ideal structural backbone for the well-organized

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• -factor receptors yet is still upstream of IKKγ, potentially by inhibition of a new target protein or novel protein–protein interaction. Using cell-based HTS reporter gene assays, a series of chemical probes were identified that selectively inhibit this unique PKC-induced NF-κB pathway without modulating

Peptides presenting the binding site of human CD4 for the HIV-1 envelope glycoprotein gp120

• Julia Meier,
• Kristin Kassler,
• Heinrich Sticht and
• Jutta Eichler

Beilstein J. Org. Chem. 2012, 8, 1858–1866, doi:10.3762/bjoc.8.214

• , which in turn will increase their affinity to the complementary protein, and, consequently, their ability to interfere with the native protein–protein interaction. Experimental Peptide synthesis Peptides were synthesized as C-terminal amides by Fmoc/t-Bu-based solid-phase synthesis on 100 mg TentaGel S

An easily accessible sulfated saccharide mimetic inhibits in vitro human tumor cell adhesion and angiogenesis of vascular endothelial cells

• Grazia Marano,
• Claas Gronewold,
• Martin Frank,
• Anette Merling,
• Christian Kliem,
• Sandra Sauer,
• Manfred Wiessler,
• Eva Frei and
• Reinhard Schwartz-Albiez

Beilstein J. Org. Chem. 2012, 8, 787–803, doi:10.3762/bjoc.8.89

• detectable carbohydrate–protein interaction, because the combined synthetic peptidic integrin ligands completely blocked cell adhesion to fibronectin, but on the other hand, cell adhesion could be inhibited with the sulfated saccharide mimetic GSF, probably by interfering with protein–protein interactions

Synthesis of fluorinated maltose derivatives for monitoring protein interaction by ¹⁹F NMR

• Michaela Braitsch,
• Hanspeter Kählig,
• Georg Kontaxis,
• Michael Fischer,
• Toshinari Kawada,
• Robert Konrat and
• Walther Schmid

Beilstein J. Org. Chem. 2012, 8, 448–455, doi:10.3762/bjoc.8.51

• -2-F-maltose-isomers; one isomer (α-gluco-type) binds to MBP and senses the protein interaction, and the nonbinding isomers (β-gluco- and/or α/β-manno-type) are utilized as internal references. Moreover, this reporter system was used for relative affinity studies of fluorinated and nonfluorinated

• studies of protein–ligand interaction interfaces. Keywords: fluorination; 19F NMR; maltose-binding protein (MBP); maltose derivatives; protein interaction; Introduction In recent years, we have witnessed significant improvements in NMR spectroscopy, especially as a powerful tool for studying protein

• relaxation properties of a small-molecular-weight reporter ligand that reversibly binds to a ligand binding domain, which in turn is fused to the interacting protein of interest. Subsequent protein–protein interaction leads to an additional increase of the molecular weight of the complex and can efficiently