0000000001056896
AUTHOR
Fabian Barthels
Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases
The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modificati…
Modular Solid-Phase Synthesis of Antiprotozoal Barnesin Derivatives
Here, we applied and optimized a solid support (SP)-based Horner-Wadsworth-Emmons reagent to prepare SP-bound vinylogous amino acids. Subsequent SP-based peptide synthesis, global deprotection, and chemical modifications yielded 14 lipodipeptides carrying vinylogous amino acids, including the natural product barnesin A (1). Biological evaluation revealed that several synthesized derivatives show micromolar to nanomolar inhibitory activity against papain-like cysteine proteases, human cathepsin L, and rhodesain.
sj-pdf-1-jla-10.1177_2472630319877374 – Supplemental material for FINDUS: An Open-Source 3D Printable Liquid-Handling Workstation for Laboratory Automation in Life Sciences
Supplemental material, sj-pdf-1-jla-10.1177_2472630319877374 for FINDUS: An Open-Source 3D Printable Liquid-Handling Workstation for Laboratory Automation in Life Sciences by Fabian Barthels, Ulrich Barthels, Marvin Schwickert and Tanja Schirmeister in SLAS Technology
BANΔIT: B’‐factor Analysis for Drug Design and Structural Biology
The analysis of B‐factor profiles from X‐ray protein structures can be utilized for structure‐based drug design since protein mobility changes have been associated with the quality of protein‐ligand interactions. With the BANΔIT (B’‐factor analysis and ΔB’ interpretation toolkit), we have developed a JavaScript‐based browser application that provides a graphical user interface for the normalization and analysis of B’‐factor profiles. To emphasize the usability for rational drug design applications, we have analyzed a selection of crystallographic protein‐ligand complexes and have given exemplary conclusions for further drug optimization including the development of a B’‐factor‐supported pha…
FINDUS: An Open-Source 3D Printable Liquid-Handling Workstation for Laboratory Automation in Life Sciences
3D-printed laboratory devices can enable ambitious research purposes even at a low-budget level. To follow this trend, here we describe the construction, calibration, and usage of the FINDUS (Fully Integrable Noncommercial Dispensing Utility System). We report the successful 3D printing and assembly of a liquid-handling workstation for less than $400. Using this setup, we achieve reliable and flexible liquid-dispensing automation with relative pipetting errors of less than 0.3%. We show our system is well suited for several showcase applications from both the biology and chemistry fields. In support of the open-source spirit, we make all 3D models, assembly instructions, and source code ava…
Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure–Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies
Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorabl…
SAR of novel benzothiazoles targeting an allosteric pocket of DENV and ZIKV NS2B/NS3 proteases
In recent years, dengue virus (DENV) and Zika virus (ZIKV), both mosquito-borne members of the Flaviviridae family, have emerged as intercontinental health issues since their vectors have spread from their tropical origins to temperate climate zones due to climate change and increasing globalization. DENV and ZIKV are positive-sense, single-stranded RNA viruses, whose genomes consist of three structural (capsid, membrane precursor, envelope) and seven non-structural (NS) proteins, all of which are initially expressed as a single precursor polyprotein. For virus maturation, the polyprotein processing is accomplished by host proteases and the viral NS2B/NS3 protease complex, whose inhibitors …
sj-pdf-1-jla-10.1177_2472630319877374 – Supplemental material for FINDUS: An Open-Source 3D Printable Liquid-Handling Workstation for Laboratory Automation in Life Sciences
Supplemental material, sj-pdf-1-jla-10.1177_2472630319877374 for FINDUS: An Open-Source 3D Printable Liquid-Handling Workstation for Laboratory Automation in Life Sciences by Fabian Barthels, Ulrich Barthels, Marvin Schwickert and Tanja Schirmeister in SLAS Technology
Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A
Abstract 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 f…
CCDC 1981158: Experimental Crystal Structure Determination
Related Article: Philipp Klein, Patrick Johè, Fabian Barthels, Annika Wagner, Stefan Tenzer, Ute Distler, Thien Anh Le, Bernd Engels, Ute A. Hellmich, Till Opatz, Tanja Schirmeister|2020|Molecules|25|2064|doi:10.3390/molecules25092064