TY - JOUR A1 - Kruse, N. A1 - Tony, H. P. A1 - Sebald, Walter T1 - Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid replacement N2 - lnterleukin-4 (IL-4) represents a prototypic lymphokine (for a recent review see Paul, 1991). It promotes differentiation of B-cells and the proliferation of T- and B-cell, and other cell types of the lymphoid system. An antagonist of human IL-4 was discovered during the studies presented here after Tyr124 of the recombinant proteinbad been substituted by an aspartic acid residue. This IL-4 variant, Y124D, bound with high affinity to the IL-4 receptor (K\(_D\) = 310 pM), but retained no detectable proliferative activity for T -<:ells and inhibited IL-4-dependent T -cell proliferation competitively (K\(_i\) = 620 pM). The loss of efficacy in variant Y124D was estimated to be > 100-fold on the basis of a weak partial agonist activity for the very sensitive induction of CD23 positive B-cells. The subsitution of Tyr124 by either phenylalanine, histidine, asparagine, Iysine or glycine resulted in partial agonist variants with unaltered receptor binding atTmity and relatively small deficiencies in efficacy. These results demoostrate that high affinity binding and signal generation can be uncoupled efticiently in a Iigand of a receptor betonging to the recently identified hematopoietin receptor family. In addition we show for the first time, that a powerful antagonist acting on the IL-4 receptor system can be derived from the IL-4 protein. KW - Biochemie KW - drug design KW - partial agonists KW - receptor signalling Y1 - 1992 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62469 ER - TY - JOUR A1 - Bajda, Marek A1 - Wieckowska, Anna A1 - Hebda, Michalina A1 - Guzior, Natalia A1 - Sotriffer, Christoph A. A1 - Malawska, Barbara T1 - Structure-Based Search for New Inhibitors of Cholinesterases JF - International Journal of Molecular Sciences N2 - Cholinesterases are important biological targets responsible for regulation of cholinergic transmission, and their inhibitors are used for the treatment of Alzheimer’s disease. To design new cholinesterase inhibitors, of different structure-based design strategies was followed, including the modification of compounds from a previously developed library and a fragment-based design approach. This led to the selection of heterodimeric structures as potential inhibitors. Synthesis and biological evaluation of selected candidates confirmed that the designed compounds were acetylcholinesterase inhibitors with \(IC_{50}\) values in the mid-nanomolar to low micromolar range, and some of them were also butyrylcholinesterase inhibitors. KW - fragment-based design KW - cholinesterases inhibitors KW - butyrylcholinesterase KW - acetylcholinesterase KW - drug design Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129423 VL - 14 IS - 3 ER - TY - JOUR A1 - Bencurova, Elena A1 - Gupta, Shishir K. A1 - Sarukhanyan, Edita A1 - Dandekar, Thomas T1 - Identification of antifungal targets based on computer modeling JF - Journal of Fungi N2 - Aspergillus fumigatus is a saprophytic, cosmopolitan fungus that attacks patients with a weak immune system. A rational solution against fungal infection aims to manipulate fungal metabolism or to block enzymes essential for Aspergillus survival. Here we discuss and compare different bioinformatics approaches to analyze possible targeting strategies on fungal-unique pathways. For instance, phylogenetic analysis reveals fungal targets, while domain analysis allows us to spot minor differences in protein composition between the host and fungi. Moreover, protein networks between host and fungi can be systematically compared by looking at orthologs and exploiting information from host–pathogen interaction databases. Further data—such as knowledge of a three-dimensional structure, gene expression data, or information from calculated metabolic fluxes—refine the search and rapidly put a focus on the best targets for antimycotics. We analyzed several of the best targets for application to structure-based drug design. Finally, we discuss general advantages and limitations in identification of unique fungal pathways and protein targets when applying bioinformatics tools. KW - Aspergillus KW - metabolic pathways KW - computational modelling KW - drug design Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197670 SN - 2309-608X VL - 4 IS - 3 ER - TY - JOUR A1 - Barthels, Fabian A1 - Marincola, Gabriella A1 - Marciniak, Tessa A1 - Konhäuser, Matthias A1 - Hammerschmidt, Stefan A1 - Bierlmeier, Jan A1 - Distler, Ute A1 - Wich, Peter R. A1 - Tenzer, Stefan A1 - Schwarzer, Dirk A1 - Ziebuhr, Wilma A1 - Schirmeister, Tanja T1 - Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A JF - ChemMedChem N2 - Staphylococcus aureus is one of the most frequent causes of nosocomial and community‐acquired infections, with drug‐resistant strains being responsible for tens of thousands of deaths per year. S. aureus sortase A inhibitors are designed to interfere with virulence determinants. We have identified disulfanylbenzamides as a new class of potent inhibitors against sortase A that act by covalent modification of the active‐site cysteine. A broad series of derivatives were synthesized to derive structure‐activity relationships (SAR). In vitro and in silico methods allowed the experimentally observed binding affinities and selectivities to be rationalized. The most active compounds were found to have single‐digit micromolar Ki values and caused up to a 66 % reduction of S. aureus fibrinogen attachment at an effective inhibitor concentration of 10 μM. This new molecule class exhibited minimal cytotoxicity, low bacterial growth inhibition and impaired sortase‐mediated adherence of S. aureus cells. KW - antibiotics KW - biofilm KW - drug design KW - sortase A Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214581 VL - 15 IS - 10 SP - 839 EP - 850 ER - TY - JOUR A1 - Welker, Armin A1 - Kersten, Christian A1 - Müller, Christin A1 - Madhugiri, Ramakanth A1 - Zimmer, Collin A1 - Müller, Patrick A1 - Zimmermann, Robert A1 - Hammerschmidt, Stefan A1 - Maus, Hannah A1 - Ziebuhr, John A1 - Sotriffer, Christoph A1 - Schirmeister, Tanja T1 - Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2 JF - ChemMedChem N2 - Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL\(^{pro}\)) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PL\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PL\(^{pro}\) are valuable starting points for the development of new pan‐coronaviral inhibitors. KW - antiviral agents KW - computational chemistry KW - drug design KW - protease inhibitors KW - structure-activity relationships Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225700 VL - 16 IS - 2 SP - 340 EP - 354 ER -