Site-specific labelling of native peptides and proteins: chemical and enzymatic strategies

• Antonio Angelastro,
• Jonathan Bargh,
• Subhajit Guria,
• Victor Laserna and
• Louis Luk

Beilstein J. Org. Chem. 2026, 22, 857–881, doi:10.3762/bjoc.22.67

• , Cardiff, CF10 3AT, UK 10.3762/bjoc.22.67 Abstract Site-specific modifications of native-sequence proteins are technologies that underpin progresses in chemical biology, diagnostics and next-generation biotherapeutics. However, the pursuit of site-specificity has often come at the expense of scalability

• chromatography, while also offering well-defined pharmacokinetic and pharmacodynamic profiles. Homogeneous batches of labelled proteins thus improve therapeutic indices and reproducibility, key determinants of clinical trial outcomes. Usability. Effective strategies act directly on native proteins, avoiding

• transformations [3][4]. However, the limited abundance of free cysteine residues in proteins has driven the development of alternative approaches targeting other chemical motifs. This review summarizes current strategies for site-specific modifications of these alternative sites, followed by a comparative

Total synthesis of the capsular polysaccharide repeating unit towards the development of a glycoconjugate vaccine against Klebsiella pneumoniae ST512

• Shuo Zhang,
• Ondřej Daněk and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2026, 22, 821–827, doi:10.3762/bjoc.22.64

• attaching glycan antigens to carrier proteins, have emerged as highly effective vaccine candidates for preventing bacterial colonization and the resulting infectious diseases [19][20][21][22][23]. While several studies have explored vaccine candidates against K. pneumoniae, no commercial vaccines are

Synthesis and biological evaluation of new brassinosteroid analogs with C-22 benzoate function

• María Núñez,
• Camila Escobar,
• Mario Párraga,
• Mauricio Soto,
• Luis Espinoza-Catalán,
• Katy Díaz and
• Andrés F. Olea

Beilstein J. Org. Chem. 2026, 22, 753–762, doi:10.3762/bjoc.22.57

• the para-position. Western blotting analyses of compounds 2α,3α-dihydroxy-5α-cholan-6-oxo-23,24-dinor-22-(4-substituted)-benzoate-type treatment on BES1 protein Western blot is a very useful, sensitive, specific and efficient technique for the detection and identification of specific proteins from a

• complex mixture of proteins. In addition, it is possible to quantify their expression by using suitable primary and secondary antibodies to visualize it. It has been established that the dephosphorylated forms of BZR1 and BES1, and their concomitant accumulation in the nucleus, control the activity in the

• main idea is to correlate the amount and form of BES1 with the activity exhibited by these analogs on the root growth assay. The results of the immunoblot analysis of proteins with an antibody specific for BES1, in roots of A. thaliana ecotype Col-0 plants are shown in Figure S67, Supporting

Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• . Compared with conventional small-molecule inhibitors, PROTACs exhibit notable advantages, particularly in achieving selectivity within highly homologous proteins. The ability to discriminate among members of such families holds broad implications for future disease treatment. In this review, we primarily

• summarize the advantages of PROTACs in conferring selectivity toward highly homologous proteins. This focus will provide a feasible strategy for developing PROTACs that selectively target highly homologous proteins and will ultimately support future therapeutic applications. Keywords: homologous protein

• ; PROTAC; protein–protein interaction; selectivity; ubiquitination; Introduction The cell is the fundamental unit of structure and function in the human body [1][2]. More than 20,000 proteins act in concert to regulate the entire cellular life process [1]. To date, dysregulated protein function has been

Regioselective approach to 5-arylsulfonylisoxazoles and their antimicrobial activity

• Artem S. Sazonov,
• Dmitry A. Vasilenko,
• Denis V. Porfiriev,
• Yuri K. Grishin,
• Rimma A. Gazzaeva,
• Alisa P. Chernyshova,
• Maxim A. Kryakvin,
• Anna A. Baranova,
• Vera A. Alferova and
• Elena B. Averina

Beilstein J. Org. Chem. 2026, 22, 592–602, doi:10.3762/bjoc.22.45

• ]. Briefly, these reporter strains express different fluorescent proteins depending on the mechanism of action of the antibiotic. In case of activation of the antibiotic-induced SOS-response, the rfp gene was expressed in the cell of the reporter strains, and disruption of the translation mechanism led to

Design and synthesis of an erdafitinib-based selective FGFR2 degrader

• Yumeng Jin,
• Shidong Wang,
• Sihan Pan,
• Shuqi Huang,
• Weichen Zhou,
• Xiaohao Huang,
• Lei Zheng and
• Lingfeng Chen

Beilstein J. Org. Chem. 2026, 22, 583–591, doi:10.3762/bjoc.22.44

• rearrangements or fusions involving FGFR2 can create novel chimeric proteins with enhanced or aberrant signaling capabilities, further driving cells towards a malignant phenotype [13][15]. Notably, FGFR2 amplification and fusions are frequently detected in patients with advanced gastric cancer and

• harnessing the intracellular endogenous protein degradation machinery. However, this technology still faces challenges in degrading membrane proteins such as FGFR2, partly due to the cell-type-specific expression differences of E3 ligases. Through systematic medicinal chemistry design and pharmacodynamic

Molecular tweezer–peptide conjugates disrupt the protein–protein interaction between survivin and histone H3 essential in mitosis

• Catherine Gsell,
• Philipp Rebmann,
• Karina Opara,
• Christine Beuck,
• Peter Bayer,
• David Bier,
• Ingrid R. Vetter and
• Thomas Schrader

Beilstein J. Org. Chem. 2026, 22, 557–567, doi:10.3762/bjoc.22.41

• cell division, this kinetochore interacts with a smaller ensemble, the chromosomal passenger complex (CPC) that constitutes an abundant component of the inner centromere [2][3]. The CPC itself is formed inside the cell nucleus and consists of the four proteins survivin, borealin, INCENP (inner

• centromere protein), and the kinase Aurora B. During mitosis, Aurora B phosphorylates important components of the kinetochore and thus exerts control over key events of the whole process. The other three proteins localize the CPC during the different mitotic phases [4]. Survivin, borealin and INCENP are

• https://doi.org/10.2210/pdb3UIH/pdb, [23]). A major problem of co-crystallizing tweezer compounds with proteins in general is the competition with the crystal packing, as illustrated by earlier crystal structures [20]. Since the "proof-of-concept" H3-peptide tweezer 1 targeted lysine 121 which is not

Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• domain within the CoREST complex. Keywords: CI-994; co-repressor complex; CoREST; cryo-EM; gold nanoparticle; HDAC; Introduction Histone deacetylase (HDAC) enzymes catalyze the hydrolysis of acetyl groups from N-acetylated lysine residues in histone proteins. HDACs are also capable of the deacetylation

• of non-histone proteins [1], and the hydrolysis of other acyl functional groups [2]. The human genome encodes 18 histone deacetylases (HDACs), which are divided into two main groups based on their catalytic mechanisms [3]. Eleven HDACs are zinc-dependent enzymes, while the remaining seven, known as

• residues. Cysteines possess thiol side chains that exhibit strong affinity for gold, enabling them to form stable bonds with metal surfaces [21]. Such interactions may disrupt the native conformation of cysteine-containing proteins or peptides, potentially impairing the structural integrity of the CoREST

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• significant negative character that enables it to form a hydrogen bonding interaction with the active site amino acid residue of the proteins. MEP analysis of compounds 7 and 8 The molecular electrostatic potential (MEP) maps of compounds 7 and 8 are depicted in Figure 6a and 6b, respectively. The MEP

• Mulliken charge analysis (MCA). Molecular docking protocol Auto Dock Tools version 1.5.7 was used for all molecular docking studies [77]. The Protein Data Bank (https://www.rcsb.org) provided the EGFR tyrosine kinase receptor proteins (PDB IDs: 1M17 and 4HJO) [73][74]. The structure of ligand 7 was

• atoms. The receptor proteins were uploaded into Auto Dock, then water molecules and co-crystallised ligands were removed from the protein. After that, polar hydrogens were added, and Kollman charges were assigned. The grid box was then generated around the active site pocket with the following

Cone p-aminocalix[4]arenes enriched with ‘clickable’ alkyne or azide functionalities

• Ilia Korniltsev,
• Vasily Bazhenov,
• Alexander Gorbunov,
• Dmitry Cheshkov,
• Stanislav Bezzubov,
• Vladimir Kovalev and
• Ivan Vatsouro

Beilstein J. Org. Chem. 2026, 22, 399–415, doi:10.3762/bjoc.22.28

• biocompatible compounds capable of interacting with proteins, nucleic acids, and polysaccharides [27][28][29][30][31], and may also mimic phosphodiesterase functions [32][33][34][35]. Beyond biorelevant structures, p-aminocalix[4]arenes serve as preorganizing platforms that may graft together four functional

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• -mimicking scaffolds are a proven strategy in the design of anticancer drugs. Many cancer-related proteins (e.g., kinases, ATPases, DNA/RNA polymerases) have binding pockets designed for purine nucleotides (ATP, GTP). Oxazolopyrimidines can compete with purines or their analogues, inhibiting enzymatic

• lone electron pair at the nitrogen atoms and protonated amino acids of proteins. However, oxazolo[5,4-d]pyrimidine forms more stable complexes, which is in good agreement with in vitro studies [10]. We have already shown the anticancer potential of 7-N-derivatives of 2,5-diaryl[1,3]oxazolo[4,5-d

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• absorption (HIA), in vitro permeability to Caco-2 cells (Caco2), in vitro binding to plasma proteins (PPB), solubility, and inhibition of CYP2D6. The following were selected as descriptors of toxicity: carcinogenicity for rats and mice, mutagenicity according to the Ames test, and cardiotoxicity by

Screwing the helical chirality through terminal peri-functionalization

• Devesh Chandra,
• Sachin and
• Upendra Sharma

Beilstein J. Org. Chem. 2026, 22, 205–212, doi:10.3762/bjoc.22.14

• ; Introduction Nature utilizes helical chirality for the inception of life. The double-helical structure of DNA and the helical conformations of proteins are key examples of the helical chirality. Inspired by these natural systems, chemists have developed methods to construct and control helicity in synthetic

Effect of a photoswitchable rotaxane on membrane permeabilization across lipid compositions

• Udyogi N. K. Conthagamage,
• Lilia Lopez,
• Zuliah A. Abdulsalam and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2498–2512, doi:10.3762/bjoc.21.192

• proteins that are responsible for essential cellular functions [1]. As a result, the function and properties of lipid membranes are significantly influenced by their lipid composition, which varies across various domains of life, including mammalian, prokaryotic, and plant cells, and even between

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• condensing abilities. Specific facial preferences are displayed as cholesterol interacts with different neighboring lipids and transmembrane proteins [33][34]. These biochemical interactions are poorly understood, so the synthesis of a «smoothed» cholesterol analogue provided an opportunity to experimentally

Synthetic study toward vibralactone

• Liang Shi,
• Jiayi Song,
• Yiqing Li,
• Jia-Chen Li,
• Shuqi Li,
• Li Ren,
• Zhi-Yun Liu and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2025, 21, 2376–2382, doi:10.3762/bjoc.21.182

• cyclization as the all-carbon quaternary center is formed in the last step. Given that the β-lactone moiety may act as a potential covalent inhibitor toward target proteins and that the sterically congested bicyclic skeleton presents a significant synthetic challenge, we herein report our synthetic study

Thiadiazino-indole, thiadiazino-carbazole and benzothiadiazino-carbazole dioxides: synthesis, physicochemical and early ADME characterization of representatives of new tri-, tetra- and pentacyclic ring systems and their intermediates

• Gyöngyvér Pusztai,
• László Poszávácz,
• Anna Vincze,
• András Marton,
• Ahmed Qasim Abdulhussein,
• Judit Halász,
• András Dancsó,
• Gyula Simig,
• György Tibor Balogh and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2220–2233, doi:10.3762/bjoc.21.169

• phosphate buffer for the “without cofactors” control. Aliquots (100 µL) were taken at zero time and at pre-defined time points of 30 and 60 minutes and quenched with an equal volume of cold acetonitrile. The samples were centrifuged at 2600 RCF for 10 minutes to pellet proteins. Supernatants were

Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads

• Scott Rice,
• Julian Chesti,
• William R. T. Mosedale,
• Megan H. Wright,
• Stephen P. Marsden,
• Terry K. Smith and
• Adam Nelson

Beilstein J. Org. Chem. 2025, 21, 1924–1931, doi:10.3762/bjoc.21.150

• , Biomedical Sciences Research Complex, University of St Andrews, St Andrews, KY16 9ST, UK 10.3762/bjoc.21.150 Abstract The value of small molecules that chemically modify proteins is increasingly being recognised and utilised in both chemical biology and drug discovery. The discovery of such chemical tools

• the discovery of small molecule modifiers for investigating and engineering proteins. Keywords: covalent probes; molecular diversity; rhodium carbenoids; Introduction Diverse sets of reactive probes can facilitate the discovery of chemical tools and drugs that chemically modify protein targets [1][2

• direct connective synthesis of diverse reactive probes. We envisage that such probes may enable chemical modification of non-cysteine residues within proteins, and may be valuable in investigating and engineering the biology of proteins. Envisaged connective synthesis of reactive probes 3 bearing S(VI

Synthesis, biological and electrochemical evaluation of glycidyl esters of phosphorus acids as potential anticancer drugs

• Almaz A. Zagidullin,
• Emil R. Bulatov,
• Mikhail N. Khrizanforov,
• Damir R. Davletshin,
• Elvina M. Gilyazova,
• Ivan A. Strelkov and
• Vasily A. Miluykov

Beilstein J. Org. Chem. 2025, 21, 1909–1916, doi:10.3762/bjoc.21.148

• . Electrochemical studies Alkylating agents are widely recognized for their ability to form covalent bonds with biological macromolecules (proteins, DNA). The literature discusses the interaction of small molecules with proteins, highlighting how linear sweep voltammetry (LSV) can be used to understand these

• disappearance of the albumin oxidation peak strongly suggests that all three investigated compounds can modify proteins under physiological conditions. Moreover, the fact that each agent was capable of this disruption aligns well with prior tests on the studied cell lines (PC-3, MCF-7, and HSF), where

• compounds 1–3 strongly indicates their ability to covalently modify nucleophilic sites in proteins. This finding underscores the potential of LSV as a rapid and effective tool for assessing alkylating reactivity, with implications for future drug development. Overall, this study offers meaningful insights

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• -linking of polymers (such as PLGA and PEG), inorganic materials (such as gold and silica), or biomolecules (lipids and proteins), enabling efficient drug loading and controlled release [66][67][68]. Among them, amphiphilic CAs that incorporate both hydrophilic groups and hydrophobic alkyl chains through

Formal synthesis of a selective estrogen receptor modulator with tetrahydrofluorenone structure using [3 + 2 + 1] cycloaddition of yne-vinylcyclopropanes and CO

• Jing Zhang,
• Guanyu Zhang,
• Hongxi Bai and
• Zhi-Xiang Yu

Beilstein J. Org. Chem. 2025, 21, 1639–1644, doi:10.3762/bjoc.21.127

• widely distributed nuclear receptor proteins and include two subtypes, ERα [3][4] and ERβ [5][6]. These receptors can bind 17β-estradiol with similar affinity, facilitating the transfer of estrogen to various tissues in the body. Due to this, 17β-estradiol as non-selective ligand has been extensively

Heterologous biosynthesis of cotylenol and concise synthesis of fusicoccane diterpenoids

• Ye Yuan,
• Zhenhua Guan,
• Xue-Jie Zhang,
• Nanyu Yao,
• Wenling Yuan,
• Yonghui Zhang,
• Ying Ye and
• Zheng Xiang

Beilstein J. Org. Chem. 2025, 21, 1489–1495, doi:10.3762/bjoc.21.111

• -inflammatory, antimicrobial, antiparasitic, and plant growth regulating activities. For instance, cotylenin A (1) and fusicoccin A (2) function as molecular glues to stabilize the interactions between 14-3-3 proteins and their binding partners in plant and animal cells [8][9][10][11][12]. It has been reported

Photoredox-catalyzed arylation of isonitriles by diaryliodonium salts towards benzamides

• Nadezhda M. Metalnikova,
• Nikita S. Antonkin,
• Tuan K. Nguyen,
• Natalia S. Soldatova,
• Alexander V. Nyuchev,
• Mikhail A. Kinzhalov and
• Pavel S. Postnikov

Beilstein J. Org. Chem. 2025, 21, 1480–1488, doi:10.3762/bjoc.21.110

• (in case of unsymmetrical iodonium salts) were studied. Keywords: arylation; benzamides; diaryliodonium salts; isonitriles; photoredox; Introduction Amides represent a crucial and ubiquitous structural motif in essential biomolecules including proteins and peptides [1], as well as in a wide array of

Studies on the syntheses of β-carboline alkaloids brevicarine and brevicolline

• Benedek Batizi,
• Patrik Pollák,
• András Dancsó,
• Péter Keglevich,
• Gyula Simig,
• Balázs Volk and
• Mátyás Milen

Beilstein J. Org. Chem. 2025, 21, 955–963, doi:10.3762/bjoc.21.79

• silico for non-peptide malignant brain tumor (MBT) antagonist activity, showing hits on three MBT-containing proteins [35]. Although Carex brevicollis DC has been observed to have a teratogenic effect on animals [1][36], which could be linked with the presence of the two mentioned β-carboline alkaloids

Dicarboxylate recognition based on ultracycle hosts through cooperative hydrogen bonding and anion–π interactions

• Wen-Hui Mi,
• Teng-Yu Huang,
• Xu-Dong Wang,
• Yu-Fei Ao,
• Qi-Qiang Wang and
• De-Xian Wang

Beilstein J. Org. Chem. 2025, 21, 884–889, doi:10.3762/bjoc.21.72

• metabolism [3][4]; cyclic peptides play critical roles in plant or bacterial defenses and as well as animal hormone signaling [5][6]; cyclic proteins exhibit diverse therapeutic functions [7]; and cyclic nucleotides are essential for molecular cloning and hold potential for disease treatment [8]. In contrast