Staudinger Ligation and Reactions – From Bioorthogonal Labeling to Next‐Generation Biopharmaceuticals

In this review, we highlight groundbreaking discoveries and applications of Staudinger reactions in the molecular life sciences, starting from the engineering of the Staudinger ligation as a bioorthogonal reaction until most recent applications in modern bioconjugation methods to generate next-generation biopharmaceuticals. Bioorthogonal reactions refer to a set of chemoselective transformations in biological environments able to take place in presence of naturally occurring functional groups. The Staudinger ligation set a new paradigm of such transformations, resulting in the development of various labeling and bioconjugation strategies for the modification of (bio-)molecules of interest.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Leibniz-Gemeinschaft http://dx.doi.org/10.13039/501100001664Einstein Stiftung Berlin http://dx.doi.org/10.13039/501100006188Peer Reviewe

Improvement in Implementation of Fiscal Policy of Russia

In this article, the authors consider the concepts of the budget consisting in public economic relations, and two main functions of the budget, such as distributive and control. The problem concerning the lack of legislative control of budget performance has been described through the analysis of the articles and appendices of the budgetary code of the Russian Federation. As a result, it has been revealed that the budgetary policy of the Russian Federation demands improvement and an individual approach to each element and direction of its formation at the present stage. The main aspects concerning the actions for the development of effective budgetary policy, increase of stability of the budget are presented in the work by means of the budgetary rules. These rules are directly related to a proper choice of the directions of fund expenditures and increase in the income of the budget due to improvement of tax administration regarding tax revenues

Hierarchical hybrid cognitive cards methodology in the decision support system development for scientific and medical centers

In this article, the authors of the ongoing study appeal to the problem of IT products development and implementation for improving the effectiveness of health institutions and organizations, namely decision support systems and expert systems. The article provides a brief description of existing approaches and justifies a methodology based on the concept of hierarchical hybrid cognitive maps, developed by the authors at the moment

Bis‐ethynylphosphonamidates as an Modular Conjugation Platform to Generate Multi‐Functional Protein‐ and Antibody‐Drug‐Conjugates

Bis-ethynylphosphonamidates allow for a simple chemoselective addition of two thiol-containing modules in a row. We describe four such bis-electrophiles that carry different functional O-substituents with tunable hydrophilicity and enable further subsequent conjugations, thus facilitating a simple protocol for constructing protein-protein conjugates. An increased spacer length between the two ethynylphosphonamidates simplifies the formation of a conjugate from two bulky proteins. We apply these reagents to obtain homogeneous Antibody-Drug-Conjugates (ADCs) from DM1 and trastuzumab with excellent cytotoxicity and selectivity for the targeted cell line. Moreover, a bis-ethynylphosphonamidate, carrying an additional alkyne for a chemoselective triple conjugation, has been subjected to fluorescent labeling of an ADC specifically at the drug site give an Antibody-Drug-Fluorophore-Conjugate (ADFC), allowing for the observation of intracellular trafficking after ADC uptake into the targeted cell.LMU centerDeutsche Forschungsgemeinschaft (DFG)Einstein Foundation Berlin http://dx.doi.org/10.13039/501100006188Boehringer-Ingelheim FoundationFonds der Chemischen IndustrieLeibniz Association http://dx.doi.org/10.13039/501100001664German Federal Ministry for Economic Affairs and EnergyEuropean Social Fund http://dx.doi.org/10.13039/501100004895Bavarian Ministry of Economic Affairs, Regional Development and Energy http://dx.doi.org/10.13039/501100020639Peer Reviewe

The antiferromagnetic insulator Ca3FeRhO6: characterization and electronic structure calculations

We investigate the antiferromagnetic insulating nature of Ca3FeRhO6 both experimentally and theoretically. Susceptibility measurements reveal a Neel temperature T_N = 20 K, and a magnetic moment of 5.3 muB/f. u., while Moessbauer spectroscopy strongly suggests that the Fe ions, located in trigonal prismatic sites, are in a 3+ high spin state. Transport measurements display a simple Arrhenius law, with an activation energy of 0.2 eV. The experimental results are interpreted with LSDA band structure calculations, which confirm the Fe 3+ state, the high-spin/low-spin scenario, the antiferromagnetic ordering, and the value for the activation energy.Comment: 5 pages, 6 figure

Atomistic insight into the essential binding event of ACE2-derived peptides to the SARS-CoV-2 spike protein

The pathogenic agent of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters into human cells through the interaction between the receptor binding domain (RBD) of its spike glycoprotein and the angiotensin-converting enzyme 2 (ACE2) receptor. Efforts have been made towards finding antivirals that block this interaction, therefore preventing infection. Here, we determined the binding affinity of ACE2-derived peptides to the RBD of SARS-CoV-2 experimentally and performed MD simulations in order to understand key characteristics of their interaction. One of the peptides, p6, binds to the RBD of SARS-CoV-2 with nM affinity. Although the ACE2-derived peptides retain conformational flexibility when bound to SARS-CoV-2 RBD, we identified residues T27 and K353 as critical anchors mediating the interaction. New ACE2-derived peptides were developed based on the p6-RBD interface analysis and expecting the native conformation of the ACE2 to be maintained. Furthermore, we found a correlation between the helicity in trifluoroethanol and the binding affinity to RBD of the new peptides. Under the hypothesis that the conservation of peptide secondary structure is decisive to the binding affinity, we developed a cyclized version of p6 which had more helicity than p6 and approximately half of its K D value

Design and functional analysis of heterobifunctional multivalent phage capsid inhibitors blocking the entry of influenza virus

Multiple conjugation of virus-binding ligands to multivalent carriers is a prominent strategy to construct highly affine virus binders for the inhibition of viral entry into host cells. In a previous study, we introduced rationally designed sialic acid conjugates of bacteriophages (Q beta) that match the triangular binding site geometry on hemagglutinin spike proteins of influenza A virions, resulting in effective infection inhibition in vitro and in vivo. In this work, we demonstrate that even partially sialylated Q beta conjugates retain the inhibitory effect despite reduced activity. These observations not only support the importance of trivalent binding events in preserving high affinity, as supported by computational modeling, but also allow us to construct heterobifunctional modalities. Capsids carrying two different sialic acid ligand-linker structures showed higher viral inhibition than their monofunctional counterparts. Furthermore, capsids carrying a fluorescent dye in addition to sialic acid ligands were used to track their interaction with cells. These findings support exploring broader applications as multivalent inhibitors in the future

(3+2)‐Cyclization Reactions of Unsaturated Phosphonites with Aldehydes and Thioketones

By exploiting the unique reactivity of ethynyl‐phosphonites we obtain novel P(V)‐containing five‐membered heterocycles via (3+2)‐cyclization reactions with aldehydes or cycloaliphatic thioketones in satisfactory to excellent yields. Whereas reactions with thioketones to yield 1,3‐thiaphospholes‐3‐oxides occur smoothly at room temperature with equimolar amounts of the starting materials in absence of any catalyst, the analogous conversions with aldehydes to generate 3‐oxides of 1,3‐oxaphospholes require addition of triethylamine as a base. We postulate a step‐wise (3+2)‐cyclization mechanism for the formation of the 1,3‐thiaphosphole ring based on DFT quantum chemical calculations. With this study, we introduce new cyclization reactions originating from unsaturated phosphonites as central synthetic building blocks to yield previously inaccessible stable phosphorus‐containing heterocycles with unexplored potential for the molecular sciences.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Alexander von Humboldt-Stiftung http://dx.doi.org/10.13039/100005156Peer Reviewe

Design and Functional Analysis of Heterobifunctional Multivalent Phage Capsid Inhibitors Blocking the Entry of Influenza Virus

Multiple conjugation of virus-binding ligands to multivalent carriers is a prominent strategy to construct highly affine virus binders for the inhibition of viral entry into host cells. In a previous study, we introduced rationally designed sialic acid conjugates of bacteriophages (Qβ) that match the triangular binding site geometry on hemagglutinin spike proteins of influenza A virions, resulting in effective infection inhibition in vitro and in vivo. In this work, we demonstrate that even partially sialylated Qβ conjugates retain the inhibitory effect despite reduced activity. These observations not only support the importance of trivalent binding events in preserving high affinity, as supported by computational modeling, but also allow us to construct heterobifunctional modalities. Capsids carrying two different sialic acid ligand–linker structures showed higher viral inhibition than their monofunctional counterparts. Furthermore, capsids carrying a fluorescent dye in addition to sialic acid ligands were used to track their interaction with cells. These findings support exploring broader applications as multivalent inhibitors in the future