@article{WelkerKerstenMuelleretal.2021,
  author    = {Welker, Armin and Kersten, Christian and M{\"u}ller, Christin and Madhugiri, Ramakanth and Zimmer, Collin and M{\"u}ller, Patrick and Zimmermann, Robert and Hammerschmidt, Stefan and Maus, Hannah and Ziebuhr, John and Sotriffer, Christoph and Schirmeister, Tanja},
  title     = {Structure-Activity Relationships of Benzamides and Isoindolines Designed as SARS-CoV Protease Inhibitors Effective against SARS-CoV-2},
  series = {ChemMedChem},
  volume    = {16},
  journal   = {ChemMedChem},
  number    = {2},
  doi       = {10.1002/cmdc.202000548},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225700},
  pages     = {340 -- 354},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{PimentelElardoBubackGulderetal.2011,
  author    = {Pimentel-Elardo, Sheila M. and Buback, Verena and Gulder, Tobias A. M. and Bugni, Tim S. and Reppart, Jason and Bringmann, Gerhard and Ireland, Chris M. and Schirmeister, Tanja and Hentschel, Ute},
  title     = {New Tetromycin Derivatives with Anti-Trypanosomal and Protease Inhibitory Activities},
  series = {Marine drugs},
  volume    = {9},
  journal   = {Marine drugs},
  number    = {10},
  doi       = {10.3390/md9101682},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141171},
  pages     = {1682-1697},
  year      = {2011},
  abstract  = {Four new tetromycin derivatives, tetromycins 1-4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001(T) cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV M(pro), and PL(pro). The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with K(i) values in the low micromolar range.},
  language  = {en}
}
@article{PimentelElardoBubackGulderetal.2011,
  author    = {Pimentel-Elardo, Sheila M. and Buback, Verena and Gulder, Tobias A. M. and Bugni, Tim S. and Reppart, Jason and Bringmann, Gerhard and Ireland, Chris M. and Schirmeister, Tanja and Hentschel, Ute},
  title     = {New Tetromycin Derivatives with Anti-Trypanosomal and Protease Inhibitory Activities},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75465},
  year      = {2011},
  abstract  = {Four new tetromycin derivatives, tetromycins 1-4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001T cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV Mpro, and PLpro. The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with Ki values in the low micromolar range.},
  subject      = {Biologie},
  language  = {en}
}
@article{OliAbdelmohsenHentscheletal.2014,
  author    = {Oli, Swarna and Abdelmohsen, Usama Ramadan and Hentschel, Ute and Schirmeister, Tanja},
  title     = {Identification of Plakortide E from the Caribbean Sponge Plakortis halichondroides as a Trypanocidal Protease Inhibitor using Bioactivity-Guided Fractionation},
  series = {MARINE DRUGS},
  volume    = {12},
  journal   = {MARINE DRUGS},
  number    = {5},
  issn      = {1660-3397},
  doi       = {10.3390/md12052614},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116536},
  pages     = {2614-2622},
  year      = {2014},
  abstract  = {In this paper, we report new protease inhibitory activity of plakortide E towards cathepsins and cathepsin-like parasitic proteases. We further report on its anti-parasitic activity against Trypanosoma brucei with an IC50 value of 5 mu M and without cytotoxic effects against J774.1 macrophages at 100 mu M concentration. Plakortide E was isolated from the sponge Plakortis halichondroides using enzyme assay-guided fractionation and identified by NMR spectroscopy and mass spectrometry. Furthermore, enzyme kinetic studies confirmed plakortide E as a non-competitive, slowly-binding, reversible inhibitor of rhodesain.},
  language  = {en}
}
@article{MuellerMetaMeidneretal.2023,
  author    = {M{\"u}ller, Patrick and Meta, Mergim and Meidner, Jan Laurenz and Schwickert, Marvin and Meyr, Jessica and Schwickert, Kevin and Kersten, Christian and Zimmer, Collin and Hammerschmidt, Stefan Josef and Frey, Ariane and Lahu, Albin and de la Hoz-Rodr{\´i}guez, Sergio and Agost-Beltr{\´a}n, Laura and Rodr{\´i}guez, Santiago and Diemer, Kira and Neumann, Wilhelm and Gonz{\`a}lez, Florenci V. and Engels, Bernd and Schirmeister, Tanja},
  title     = {Investigation of the compatibility between warheads and peptidomimetic sequences of protease inhibitors — a comprehensive reactivity and selectivity study},
  series = {International Journal of Molecular Sciences},
  volume    = {24},
  journal   = {International Journal of Molecular Sciences},
  number    = {8},
  issn      = {1422-0067},
  doi       = {10.3390/ijms24087226},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313596},
  year      = {2023},
  abstract  = {Covalent peptidomimetic protease inhibitors have gained a lot of attention in drug development in recent years. They are designed to covalently bind the catalytically active amino acids through electrophilic groups called warheads. Covalent inhibition has an advantage in terms of pharmacodynamic properties but can also bear toxicity risks due to non-selective off-target protein binding. Therefore, the right combination of a reactive warhead with a well-suited peptidomimetic sequence is of great importance. Herein, the selectivities of well-known warheads combined with peptidomimetic sequences suited for five different proteases were investigated, highlighting the impact of both structure parts (warhead and peptidomimetic sequence) for affinity and selectivity. Molecular docking gave insights into the predicted binding modes of the inhibitors inside the binding pockets of the different enzymes. Moreover, the warheads were investigated by NMR and LC-MS reactivity assays against serine/threonine and cysteine nucleophile models, as well as by quantum mechanics simulations.},
  language  = {en}
}
@article{KleinJoheWagneretal.2020,
  author    = {Klein, Philipp and Johe, Patrick and Wagner, Annika and Jung, Sascha and K{\"u}hlborn, Jonas and Barthels, Fabian and Tenzer, Stefan and Distler, Ute and Waigel, Waldemar and Engels, Bernd and Hellmich, Ute A. and Opatz, Till and Schirmeister, Tanja},
  title     = {New cysteine protease inhibitors: electrophilic (het)arenes and unexpected prodrug identification for the Trypanosoma protease rhodesain},
  series = {Molecules},
  volume    = {25},
  journal   = {Molecules},
  number    = {6},
  issn      = {1420-3049},
  doi       = {10.3390/molecules25061451},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203380},
  year      = {2020},
  abstract  = {Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the S\(_N\)Ar addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly active prodrug inhibitor, the liberated carboxylic acid represents a highly potent inhibitor of rhodesain (K\(_i\) = 4.0 nM). The simulations indicate that, after the cleavage of the ester, the carboxylic acid leaves the active site and re-binds to the enzyme in an orientation that allows the formation of a very stable π-complex between the catalytic dyad (Cys-25/His-162) of rhodesain and the electrophilic aromatic moiety. The reversible inhibition mode results because the S\(_N\)Ar reaction, which is found in an alkaline solvent containing a low molecular weight thiol, is hindered within the enzyme due to the presence of the positively charged imidazolium ring of His-162. Comparisons between measured and calculated NMR shifts support this interpretation},
  language  = {en}
}
@article{KleinBarthelsJoheetal.2020,
  author    = {Klein, Philipp and Barthels, Fabian and Johe, Patrick and Wagner, Annika and Tenzer, Stefan and Distler, Ute and Le, Thien Anh and Schmid, Paul and Engel, Volker and Engels, Bernd and Hellmich, Ute A. and Opatz, Till and Schirmeister, Tanja},
  title     = {Naphthoquinones as covalent reversible inhibitors of cysteine proteases — studies on inhibition mechanism and kinetics},
  series = {Molecules},
  volume    = {25},
  journal   = {Molecules},
  number    = {9},
  issn      = {1420-3049},
  doi       = {10.3390/molecules25092064},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203791},
  year      = {2020},
  abstract  = {The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4-naphthoquinones with a dipeptidic recognition motif (HN-l-Phe-l-Leu-OR) in the 2-position and an electron-withdrawing group (EWG) in the 3-position is presented. One of the compound representatives, namely the acid with EWG = CN and with R = H proved to be a highly potent rhodesain inhibitor with nanomolar affinity. The respective benzyl ester (R = Bn) was found to be hydrolyzed by the target enzyme itself yielding the free acid. Detailed kinetic and mass spectrometry studies revealed a reversible covalent binding mode. Theoretical calculations with different density functionals (DFT) as well as wavefunction-based approaches were performed to elucidate the mode of action.},
  language  = {en}
}
@article{BarthelsMarincolaMarciniaketal.2020,
  author    = {Barthels, Fabian and Marincola, Gabriella and Marciniak, Tessa and Konh{\"a}user, Matthias and Hammerschmidt, Stefan and Bierlmeier, Jan and Distler, Ute and Wich, Peter R. and Tenzer, Stefan and Schwarzer, Dirk and Ziebuhr, Wilma and Schirmeister, Tanja},
  title     = {Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A},
  series = {ChemMedChem},
  volume    = {15},
  journal   = {ChemMedChem},
  number    = {10},
  doi       = {10.1002/cmdc.201900687},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214581},
  pages     = {839 -- 850},
  year      = {2020},
  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 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.},
  language  = {en}
}
@article{AbdelmohsenSzesnyOthmanetal.2012,
  author    = {Abdelmohsen, Usama Ramadan and Szesny, Matthias and Othman, Eman Maher and Schirmeister, Tanja and Grond, Stepanie and Stopper, Helga and Hentschel, Ute},
  title     = {Antioxidant and Anti-Protease Activities of Diazepinomicin from the Sponge-Associated Micromonospora Strain RV115},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76279},
  year      = {2012},
  abstract  = {Diazepinomicin is a dibenzodiazepine alkaloid with an unusual structure among the known microbial metabolites discovered so far. Diazepinomicin was isolated from the marine sponge-associated strain Micromonospora sp. RV115 and was identified by spectroscopic analysis and by comparison to literature data. In addition to its interesting preclinical broad-spectrum antitumor potential, we report here new antioxidant and anti-protease activities for this compound. Using the ferric reducing antioxidant power (FRAP) assay, a strong antioxidant potential of diazepinomicin was demonstrated. Moreover, diazepinomicin showed a significant antioxidant and protective capacity from genomic damage induced by the reactive oxygen species hydrogen peroxide in human kidney (HK-2) and human promyelocytic (HL-60) cell lines. Additionally, diazepinomicin inhibited the proteases rhodesain and cathepsin L at an IC50 of 70-90 μM. It also showed antiparasitic activity against trypomastigote forms of Trypanosoma brucei with an IC50 of 13.5 μM. These results showed unprecedented antioxidant and anti-protease activities of diazepinomicin, thus further highlighting its potential as a future drug candidate.},
  subject      = {Biologie},
  language  = {en}
}