scholarly journals KBE009: A Bestatin-Like Inhibitor of the Trypanosoma cruzi Acidic M17 Aminopeptidase With In Vitro Anti-Trypanosomal Activity

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1037
Author(s):  
Jorge González-Bacerio ◽  
Irina Arocha ◽  
Mirtha Elisa Aguado ◽  
Yanira Méndez ◽  
Sabrina Marsiccobetre ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Rational Design ◽  
Specific Effect ◽  
Dermal Fibroblasts ◽  
Aminopeptidase Activity ◽  
Geometrical Shape ◽  
Starting Point ◽  
Insight Into ◽  
Leucyl Aminopeptidase

Chagas disease, caused by the kinetoplastid parasite Trypanosoma cruzi, is a human tropical illness mainly present in Latin America. The therapies available against this disease are far from ideal. Proteases from pathogenic protozoan have been considered as good drug target candidates. T. cruzi acidic M17 leucyl-aminopeptidase (TcLAP) mediates the major parasite’s leucyl-aminopeptidase activity and is expressed in all parasite stages. Here, we report the inhibition of TcLAP (IC50 = 66.0 ± 13.5 µM) by the bestatin-like peptidomimetic KBE009. This molecule also inhibited the proliferation of T. cruzi epimastigotes in vitro (EC50 = 28.1 ± 1.9 µM) and showed selectivity for the parasite over human dermal fibroblasts (selectivity index: 4.9). Further insight into the specific effect of KBE009 on T. cruzi was provided by docking simulation using the crystal structure of TcLAP and a modeled human orthologous, hLAP3. The TcLAP-KBE009 complex is more stable than its hLAP3 counterpart. KBE009 adopted a better geometrical shape to fit into the active site of TcLAP than that of hLAP3. The drug-likeness and lead-likeness in silico parameters of KBE009 are satisfactory. Altogether, our results provide an initial insight into KBE009 as a promising starting point compound for the rational design of drugs through further optimization.

scholarly journals SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling

2021 ◽  
Author(s):  
Scott B Biering ◽  
Francielle Tramontini Gomes de Sousa ◽  
Laurentia V. Tjang ◽  
Felix Pahmeier ◽  
Richard Ruan ◽  
...  
Keyword(s):  
Transcriptional Response ◽  
Barrier Dysfunction ◽  
Vascular Leak ◽  
Endothelial Barrier Dysfunction ◽  
Mechanistic Insight ◽  
Starting Point ◽  
Signaling Axis ◽  
Insight Into

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of this pathology are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to trigger barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Our findings suggest that S interactions with barrier cells are a contributing factor to COVID-19 disease severity and offer mechanistic insight into SARS-CoV-2 triggered vascular leak, providing a starting point for development of therapies targeting COVID-19 pathogenesis.

scholarly journals Cinnamides Target Leishmania amazonensis Arginase Selectively

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5271
Author(s):  
Edson Roberto da Silva ◽  
Júlio Abel Alfredo dos Santos Simone Come ◽  
Simone Brogi ◽  
Vincenzo Calderone ◽  
Giulia Chemi ◽  
...  
Keyword(s):  
Caffeic Acid ◽  
Selective Inhibition ◽  
Leishmania Amazonensis ◽  
The Other ◽  
Computational Investigation ◽  
Weak Inhibitor ◽  
Starting Point ◽  
Insight Into ◽  
Caffeic Acid Phenethyl Amide

Caffeic acid and related natural compounds were previously described as Leishmania amazonensis arginase (L-ARG) inhibitors, and against the whole parasite in vitro. In this study, we tested cinnamides that were previously synthesized to target human arginase. The compound caffeic acid phenethyl amide (CAPA), a weak inhibitor of human arginase (IC50 = 60.3 ± 7.8 μM) was found to have 9-fold more potency against L-ARG (IC50 = 6.9 ± 0.7 μM). The other compounds that did not inhibit human arginase were characterized as L-ARG, showing an IC50 between 1.3–17.8 μM, and where the most active was compound 15 (IC50 = 1.3 ± 0.1 μM). All compounds were also tested against L. amazonensis promastigotes, and only the compound CAPA showed an inhibitory activity (IC50 = 80 μM). In addition, in an attempt to gain an insight into the mechanism of competitive L-ARG inhibitors, and their selectivity over mammalian enzymes, we performed an extensive computational investigation, to provide the basis for the selective inhibition of L-ARG for this series of compounds. In conclusion, our results indicated that the compounds based on cinnamoyl or 3,4-hydroxy cinnamoyl moiety could be a promising starting point for the design of potential antileishmanial drugs based on selective L-ARG inhibitors.

scholarly journals 7-Chloroquinolin-4-yl Arylhydrazone Derivatives: Synthesis and Antifungal Activity

2011 ◽  
Vol 11 ◽  
pp. 1489-1495 ◽  
Author(s):  
Auri R. Duval ◽  
Pedro H. Carvalho ◽  
Maieli C. Soares ◽  
Daniela P. Gouvêa ◽  
Geonir M. Siqueira ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Rational Design ◽  
Antifungal Agents ◽  
Inhibitory Concentration ◽  
First Line ◽  
Minimum Fungicidal Concentration ◽  
Starting Point ◽  
Line Drug ◽  
In Vitro Antifungal Activity

Fifteen 7-chloro-4-arylhydrazonequinolines have been evaluated for their in vitro antifungal activity against eight oral fungi:Candida albicans, C. parapsilosis, C. lipolytica, C. tropicalis, C. famata, C. glabrata, Rhodutorula mucilaginosa, andR. glutinis. Several compounds exhibited minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) activities comparable with the first-line drug fluconazole. These results could be considered as an important starting point for the rational design of new antifungal agents.

scholarly journals Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6644
Author(s):  
Giorgia Giorgini ◽  
Gianmarco Mangiaterra ◽  
Nicholas Cedraro ◽  
Emiliano Laudadio ◽  
Giulia Sabbatini ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
In Silico ◽  
Rational Design ◽  
Specific Binding ◽  
In Silico Analysis ◽  
In Vitro Assays ◽  
Binding Modes ◽  
Starting Point ◽  
Berberine Derivatives

The natural alkaloid berberine has been demonstrated to inhibit the Pseudomonas aeruginosa multidrug efflux system MexXY-OprM, which is responsible for tobramycin extrusion by binding the inner membrane transporter MexY. To find a structure with improved inhibitory activity, we compared by molecular dynamics investigations the binding affinity of berberine and three aromatic substituents towards the three polymorphic sequences of MexY found in P. aeruginosa (PAO1, PA7, and PA14). The synergy of the combinations of berberine or berberine derivatives/tobramycin against the same strains was then evaluated by checkerboard and time-kill assays. The in silico analysis evidenced different binding modes depending on both the structure of the berberine derivative and the specific MexY polymorphism. In vitro assays showed an evident MIC reduction (32-fold and 16-fold, respectively) and a 2–3 log greater killing effect after 2 h of exposure to the combinations of 13-(2-methylbenzyl)- and 13-(4-methylbenzyl)-berberine with tobramycin against the tobramycin-resistant strain PA7, a milder synergy (a 4-fold MIC reduction) against PAO1 and PA14, and no synergy against the ΔmexXY strain K1525, confirming the MexY-specific binding and the computational results. These berberine derivatives could thus be considered new hit compounds to select more effective berberine substitutions and their common path of interaction with MexY as the starting point for the rational design of novel MexXY-OprM inhibitors.

scholarly journals Search of Allosteric Inhibitors and Associated Proteins of an AKT-like Kinase from Trypanosoma cruzi

2018 ◽  
Vol 19 (12) ◽  
pp. 3951 ◽  
Author(s):  
Rodrigo Ochoa ◽  
Cristian Rocha-Roa ◽  
Marcel Marín-Villa ◽  
Sara Robledo ◽  
Rubén Varela-M
Keyword(s):  
Trypanosoma Cruzi ◽  
Signaling Pathway ◽  
Intracellular Signaling ◽  
Rational Design ◽  
Interaction Network ◽  
Pleckstrin Homology Domain ◽  
Intracellular Signaling Pathway ◽  
Protein Protein Interaction ◽  
Associated Proteins

Proteins associated to the PI3K/AKT/mTOR signaling pathway are widely used targets for cancer treatment, and in recent years they have also been evaluated as putative targets in trypanosomatids parasites, such as Trypanosoma cruzi. Here, we performed a virtual screening approach to find candidates that can bind regions on or near the Pleckstrin homology domain of an AKT-like protein in T. cruzi. The compounds were also evaluated in vitro. The in silico and experimental results allowed us to identify a set of compounds that can potentially alter the intracellular signaling pathway through the AKT-like kinase of the parasite; among them, a derivative of the pyrazolopyridine nucleus with an IC50 of 14.25 ± 1.00 μM against amastigotes of T. cruzi. In addition, we built a protein–protein interaction network of T. cruzi to understand the role of the AKT-like protein in the parasite, and look for additional proteins that can be postulated as possible novel molecular targets for the rational design of compounds against T. cruzi.

Synthesis, 2D-QSAR Studies and Biological Evaluation of Quinazoline Derivatives as Potent Anti-Trypanosoma cruzi Agents

2019 ◽  
Vol 15 (3) ◽  
pp. 265-276 ◽  
Author(s):  
Mariela Bollini ◽  
Ana M. Bruno ◽  
María E. Niño ◽  
Juan J. Casal ◽  
Leandro D. Sasiambarrena ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Chronic Phase ◽  
Biological Evaluation ◽  
Significant Activity ◽  
Qsar Studies ◽  
2D Qsar ◽  
Starting Point ◽  
Quinazoline Derivatives

Background: Chagas disease affects about 7 million people worldwide. Only two drugs are currently available for the treatment for this parasite disease, namely, benznidazol (Bzn) and nifurtimox (Nfx). Both drugs have limited curative power in the chronic phase of the disease. Therefore, continuous research is an urgent need so as to discover novel therapeutic alternatives. Objective: The development of safer and more efficient therapeutic anti-T. cruzi drugs continues to be a major goal in trypanocidal chemotherapy. Method: Synthesis, 2D-QSAR and drug-like physicochemical properties of a set of quinazolinone and quinazoline derivatives were studied as trypanocidal agents. All compounds were screened in vitro against Trypanosoma cruzi (Tulahuen strain, Tul 2 stock) epimastigotes and bloodstream trypomastigotes. Results: Out of 34 compounds synthesized and tested, six compounds (5a, 5b, 9b, 9h, 13f and 13p) displayed significant activity against both epimastigotes and tripomastigotes, without exerting toxicity on Vero cells. Conclusion: The antiprotozoal activity of these quinazolinone and quinazoline derivatives represents an interesting starting point for a medicinal chemistry program aiming at the development of novel chemotherapies for Chagas disease.

scholarly journals Further Insight into Crystal Structures of Escherichia coli IspH/LytB in Complex with Two Potent Inhibitors of the MEP Pathway: A Starting Point for Rational Design of New Antimicrobials

ChemBioChem ◽  
2017 ◽  
Vol 18 (21) ◽  
pp. 2137-2144 ◽  
Author(s):  
Franck Borel ◽  
Elodie Barbier ◽  
Sergiy Krasutsky ◽  
Karnjapan Janthawornpong ◽  
Philippe Chaignon ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Crystal Structures ◽  
Rational Design ◽  
Mep Pathway ◽  
Starting Point ◽  
Insight Into

scholarly journals Synthesis and Antitubercular Activity of Heteroaromatic Isonicotinoyl and 7-Chloro-4-Quinolinyl Hydrazone Derivatives

2010 ◽  
Vol 10 ◽  
pp. 1347-1355 ◽  
Author(s):  
Marcelle de L. Ferreira ◽  
Raoni S.B. Gonçalves ◽  
Laura N. de F. Cardoso ◽  
Carlos R. Kaiser ◽  
Andre L.P. Candéa ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Rational Design ◽  
Inhibitory Concentration ◽  
Antitubercular Activity ◽  
First Line ◽  
Starting Point

Two series ofN’(E)-heteroaromatic-isonicotinohydrazide derivatives (3a-f and 4a-b) and 1-(7-chloroquinolin-4-yl)-2-[(heteroaromatic)methylene]hydrazone derivatives (5a-f and 6a-b) have been synthesized and evaluated for theirin vitroantibacterial activity againstMycobacterium tuberculosisH37Rv. Several compounds were noncytotoxic and exhibited significant minimum inhibitory concentration (MIC) activity (3.12, 2.50, 1.25, or 0.60 μg/mL), which can be compared to that of the first-line drugs ethambutol (3.12 μg/mL) and rifampicin (2.0 μg/ml). These results can be considered an important starting point for the rational design of new leads for anti-TB compounds.

Unusual dimeric flavonoids from Arrabidaea brachypoda with very significant in vitro and in vivo anti-Trypanosoma cruzi activity

Planta Medica ◽  
2014 ◽  
Vol 80 (16) ◽  
Author(s):  
C Quitino-da-Rocha ◽  
E Ferreira-Queiroz ◽  
C Santana-Meira ◽  
DR Magalhães-Moreira ◽  
M Botelho-Pereira-Soares ◽  
...  
Keyword(s):  
Trypanosoma Cruzi

The Word Class Adjective in English Business Magazines Online

2018 ◽  
Vol 6 (2) ◽  
pp. 99-115
Author(s):  
Borislav Marušić ◽  
Sanda Katavić-Čaušić
Keyword(s):  
Empirical Study ◽  
Empirical Analysis ◽  
Word Formation ◽  
Word Class ◽  
Business English ◽  
Starting Point ◽  
Comprehensive Picture ◽  
English Syntax ◽  
The Empirical Analysis ◽  
Insight Into

Abstract The aim of this paper is to research the word class adjective in one sequence of the ESP: Business English, more precisely English business magazines online. It is an empirical study on the corpus taken from a variety of business magazines online. The empirical analysis allows a comprehensive insight into the word class adjective in this variety of Business English and makes its contribution to English syntax, semantics and word formation. The syntactic part analyses the adjective position in the sentence. The semantic part of the study identifies the most common adjectives that appear in English business magazines online. Most of the analysis is devoted to the word formation of the adjectives found in the corpus. The corpus is analysed in such a way that it enables its division into compounds, derivatives and conversions. The results obtained in this way will give a comprehensive picture of the word class adjective in this type of Business English and can act as a starting point for further research of the word class adjective.

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