14117
2011
eng
1682-1697
10
9
article
1
2016-11-30
--
--
New Tetromycin Derivatives with Anti-Trypanosomal and Protease Inhibitory Activities
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.
Marine drugs
10.3390/md9101682
urn:nbn:de:bvb:20-opus-141171
Mar. Drugs 2011, 9, 1682-1697; doi:10.3390/md9101682
Sheila M. Pimentel-Elardo
Verena Buback
Tobias A. M. Gulder
Tim S. Bugni
Jason Reppart
Gerhard Bringmann
Chris M. Ireland
Tanja Schirmeister
Ute Hentschel
eng
uncontrolled
cysteine protease
eng
uncontrolled
drugs
eng
uncontrolled
streptomyces
eng
uncontrolled
discovery
eng
uncontrolled
anti-trypanosomal
eng
uncontrolled
protease inhibition
eng
uncontrolled
Streptomyces axinellae
eng
uncontrolled
marine sponge
eng
uncontrolled
tetromycin
Organische Chemie
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Institut für Organische Chemie
Institut für Pharmazie und Lebensmittelchemie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14117/098_Pimentel-Elardo_MARINE-DRUGS.pdf
6386
2011
eng
article
1
2013-01-29
--
--
New Tetromycin Derivatives with Anti-Trypanosomal and Protease Inhibitory Activities
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.
urn:nbn:de:bvb:20-opus-75465
7546
In: Marine Drugs (2011) 9, 1682-1697; doi:10.3390/md9101682
Sheila M. Pimentel-Elardo
Verena Buback
Tobias A. M. Gulder
Tim S. Bugni
Jason Reppart
Gerhard Bringmann
Chris M. Ireland
Tanja Schirmeister
Ute Hentschel
deu
swd
Biologie
eng
uncontrolled
tetromycin
eng
uncontrolled
anti-trypanosomal
eng
uncontrolled
protease inhibition
eng
uncontrolled
Streptomyces axinellae
eng
uncontrolled
marine sponge
Medizin und Gesundheit
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6386/Pimentel_Elardo_marinedrugs_09_01682_v3.pdf
11653
2014
eng
2614-2622
5
12
article
1
2015-07-23
--
--
Identification of Plakortide E from the Caribbean Sponge Plakortis halichondroides as a Trypanocidal Protease Inhibitor using Bioactivity-Guided Fractionation
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.
MARINE DRUGS
10.3390/md12052614
1660-3397
24798927
urn:nbn:de:bvb:20-opus-116536
Marine Drugs 2014, 12, 2614-2622; doi:10.3390/md12052614 marine
Swarna Oli
Usama Ramadan Abdelmohsen
Ute Hentschel
Tanja Schirmeister
eng
uncontrolled
plakortis halichondroides
eng
uncontrolled
plakortide E.
eng
uncontrolled
protease inhibitor
eng
uncontrolled
slowly-binding reversible inhibitor
eng
uncontrolled
cathepsin
eng
uncontrolled
trypanosoma brucei
eng
uncontrolled
cysteine protease
eng
uncontrolled
malaria parasites
eng
uncontrolled
cathepsin-L
eng
uncontrolled
in-vitro
eng
uncontrolled
rhodesain
Wirbellose des Meeres und der Meeresküste
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11653/083_Swarna_Marine_Drugs.pdf
6582
2012
eng
article
1
2013-04-30
--
--
Antioxidant and Anti-Protease Activities of Diazepinomicin from the Sponge-Associated Micromonospora Strain RV115
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.
urn:nbn:de:bvb:20-opus-76279
7627
In: Marine Drugs (2012) 10: 10, 2208-2221, doi:10.3390/md10102208
Usama Ramadan Abdelmohsen
Matthias Szesny
Eman Maher Othman
Tanja Schirmeister
Stepanie Grond
Helga Stopper
Ute Hentschel
deu
swd
Biologie
eng
uncontrolled
diazepinomicin
eng
uncontrolled
anti-protease
eng
uncontrolled
antioxidant
eng
uncontrolled
actinomycetes
eng
uncontrolled
Micromonospora
Biowissenschaften; Biologie
open_access
Julius-von-Sachs-Institut für Biowissenschaften
Förderzeitraum 2012
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6582/073_marinedrugs_10_02208.pdf
22570
2021
eng
340
354
2
16
article
1
--
--
--
Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2
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.
ChemMedChem
10.1002/cmdc.202000548
urn:nbn:de:bvb:20-opus-225700
2021-02-22T11:58:59+00:00
sword
swordwue
attachment; filename=deposit.zip
1dcbb4325d5ee5142e9fa71ffea113e5
ChemMedChem 2021, 16(2):340-354. DOI: 10.1002/cmdc.202000548
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Armin Welker
Christian Kersten
Christin Müller
Ramakanth Madhugiri
Collin Zimmer
Patrick Müller
Robert Zimmermann
Stefan Hammerschmidt
Hannah Maus
John Ziebuhr
Christoph Sotriffer
Tanja Schirmeister
eng
uncontrolled
antiviral agents
eng
uncontrolled
computational chemistry
eng
uncontrolled
drug design
eng
uncontrolled
protease inhibitors
eng
uncontrolled
structure-activity relationships
Chemie und zugeordnete Wissenschaften
Medizin und Gesundheit
open_access
Institut für Pharmazie und Lebensmittelchemie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/22570/CMDC_CMDC202000548.pdf
20338
2020
eng
6
25
article
1
--
2020-03-23
--
New cysteine protease inhibitors: electrophilic (het)arenes and unexpected prodrug identification for the Trypanosoma protease rhodesain
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
Molecules
1420-3049
10.3390/molecules25061451
urn:nbn:de:bvb:20-opus-203380
swordwue
2020-04-29T01:58:12+00:00
attachment; filename=deposit.zip
053402a72b9f43576fcdd98272aede9c
Molecules (2020) 25:6, 1451. https://doi.org/10.3390/molecules25061451
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Philipp Klein
Patrick Johe
Annika Wagner
Sascha Jung
Jonas Kühlborn
Fabian Barthels
Stefan Tenzer
Ute Distler
Waldemar Waigel
Bernd Engels
Ute A. Hellmich
Till Opatz
Tanja Schirmeister
eng
uncontrolled
cysteine protease
eng
uncontrolled
rhodesain
eng
uncontrolled
electrophilic (het)arene
eng
uncontrolled
nucleophilic aromatic substitution
eng
uncontrolled
Meisenheimer complex
eng
uncontrolled
π-complex
eng
uncontrolled
prodrug
Chemie und zugeordnete Wissenschaften
open_access
Institut für Physikalische und Theoretische Chemie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20338/molecules-25-01451-v2.pdf
20379
2020
eng
9
25
article
1
--
2020-04-28
--
Naphthoquinones as covalent reversible inhibitors of cysteine proteases — studies on inhibition mechanism and kinetics
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.
Molecules
1420-3049
10.3390/molecules25092064
urn:nbn:de:bvb:20-opus-203791
swordwue
2020-05-07T12:56:36+00:00
attachment; filename=deposit.zip
8cda95bfbb5a51cd06c0b41059e8acbc
Molecules (2020) 25:9, 2064. https://doi.org/10.3390/molecules25092064
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Philipp Klein
Fabian Barthels
Patrick Johe
Annika Wagner
Stefan Tenzer
Ute Distler
Thien Anh Le
Paul Schmid
Volker Engel
Bernd Engels
Ute A. Hellmich
Till Opatz
Tanja Schirmeister
eng
uncontrolled
protease
eng
uncontrolled
rhodesain
eng
uncontrolled
covalent reversible inhibition
eng
uncontrolled
1,4-naphthoquinone
eng
uncontrolled
nucleophilic addition
eng
uncontrolled
prodrug
Chemie und zugeordnete Wissenschaften
open_access
Institut für Physikalische und Theoretische Chemie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/20379/molecules-25-02064-v2.pdf
21458
2020
eng
839
850
10
15
article
1
--
--
--
Asymmetric Disulfanylbenzamides as Irreversible and Selective Inhibitors of Staphylococcus aureus Sortase A
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.
ChemMedChem
10.1002/cmdc.201900687
urn:nbn:de:bvb:20-opus-214581
swordwue
2020-10-26T10:06:00+00:00
attachment; filename=deposit.zip
e41b25fb8a830249f80a4c5bebfabc52
ChemMedChem 2020, 15(10):839–850. DOI: 10.1002/cmdc.201900687
false
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
Fabian Barthels
Gabriella Marincola
Tessa Marciniak
Matthias Konhäuser
Stefan Hammerschmidt
Jan Bierlmeier
Ute Distler
Peter R. Wich
Stefan Tenzer
Dirk Schwarzer
Wilma Ziebuhr
Tanja Schirmeister
eng
uncontrolled
antibiotics
eng
uncontrolled
biofilm
eng
uncontrolled
drug design
eng
uncontrolled
sortase A
Chemie und zugeordnete Wissenschaften
open_access
Institut für Molekulare Infektionsbiologie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/21458/CMDC_CMDC201900687.pdf
31359
2023
eng
8
24
article
1
--
2023-04-13
--
Investigation of the compatibility between warheads and peptidomimetic sequences of protease inhibitors — a comprehensive reactivity and selectivity study
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.
International Journal of Molecular Sciences
1422-0067
10.3390/ijms24087226
urn:nbn:de:bvb:20-opus-313596
2023-05-05T10:53:22+00:00
sword
swordwue
attachment; filename=deposit.zip
97130647bd10a2d0c06acd6efed8caba
International Journal of Molecular Sciences (2023) 24:8, 7226. https://doi.org/10.3390/ijms24087226
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Patrick Müller
Mergim Meta
Jan Laurenz Meidner
Marvin Schwickert
Jessica Meyr
Kevin Schwickert
Christian Kersten
Collin Zimmer
Stefan Josef Hammerschmidt
Ariane Frey
Albin Lahu
Sergio de la Hoz-Rodríguez
Laura Agost-Beltrán
Santiago Rodríguez
Kira Diemer
Wilhelm Neumann
Florenci V. Gonzàlez
Bernd Engels
Tanja Schirmeister
eng
uncontrolled
covalent inhibitors
eng
uncontrolled
in vitro study
eng
uncontrolled
protease inhibitors
eng
uncontrolled
peptidomimetic sequence
eng
uncontrolled
warhead
eng
uncontrolled
reactivity and selectivity study
Chemie und zugeordnete Wissenschaften
open_access
Institut für Physikalische und Theoretische Chemie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/31359/ijms-24-07226-v3.pdf