Design, Synthesis and In Vitro Investigation of Novel Basic Celastrol Carboxamides as Bio-Inspired Leishmanicidal Agents Endowed with Inhibitory Activity against Leishmania Hsp90.
Ivan Bassanini,Silvia Parapini,Erica Elisa Ferrandi,Elena Gabriele,Nicoletta Basilico,Donatella Taramelli,Anna Sparatore +6 more
- 05 Jan 2021
- Vol. 11, Iss: 1, pp 56
TL;DR: In this paper, triterpene celastrol (CE) is used as lead compound for the design and synthesis of a panel of eleven CE carboxamides that were tested in vitro for their growth inhibitory activity against Leishmania infantum and L.tropica parasites.
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Abstract: The natural triterpene celastrol (CE) is here used as lead compound for the design and synthesis of a panel of eleven CE carboxamides that were tested in vitro for their growth inhibitory activity against Leishmania infantum and L.tropica parasites. Among them, in vitro screening identified four basic CE carboxamides endowed with nanomolar leishmanicidal activity, against both the promastigotes and the intramacrophage Leishmania amastigotes forms. These compounds also showed low toxicity toward two human (HMEC-1 and THP-1) and one murine (BMDM) cell lines. Interestingly, the most selective CE analogue (compound 3) was also endowed with the ability to inhibit the ATPase activity of the Leishmania protein chaperone Hsp90 as demonstrated by the in vitro assay conducted on a purified, full-length recombinant protein. Preliminary investigations by comparing it with the naturally occurring Hsp90 active site inhibitor Geldanamycin (GA) in two different in vitro experiments were performed. These promising results set the basis for a future biochemical investigation of the mode of interaction of celastrol and CE-inspired compounds with Leishmania Hsp90.
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Citations
Pan- and isoform-specific inhibition of Hsp90: Design strategy and recent advances.
Jing Yu,Chao Zhang,Chun Song +2 more
TL;DR: In this paper , the authors summarized classic pan-inhibitors of heat shock protein 90 based on the classification of binding sites and illustrated design strategies applied in the drug discovery, including their discovery processes and potential indications.
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Celastrol: A lead compound that inhibits SARS‐CoV‐2 replication, the activity of viral and human cysteine proteases, and virus‐induced IL‐6 secretion
Carlos Alessandro Fuzo,Ronaldo B. Martins,Thais Fernanda de Campos Fraga-Silva,Martin K. Amstalden,Thais Canassa De Leo,Juliano de Paula Souza,Thais Martins de Lima,Lúcia Helena Faccioli,Debora N. Okamoto,Maria A. Juliano,Suzelei C. França,Luiz Juliano,Vânia Luiza Deperon Bonato,Eurico Arruda,Marcelo Dias-Baruffi +14 more
TL;DR: Celastrol is a promising lead compound to develop new drug candidates to face COVID‐19 due to its ability to suppress SARS‐CoV‐2 replication and IL‐6 production in infected cells.
11
In vitro activity and cell death mechanism induced by acrylonitrile derivatives against Leishmania amazonensis.
Carlos J. Bethencourt-Estrella,Samuel Delgado-Hernández,Atteneri López-Arencibia,Desirée San Nicolás-Hernández,David Tejedor,Fernando García-Tellado,Jacob Lorenzo-Morales,José E. Piñero +7 more
TL;DR: In this paper , 32 acrylonitriles were studied in vitro against leishmaniasis amazonensis and three compounds Q20 (12.41), Q29 (11.2) and Q31 (10.56) had better selectivity than the reference compound, miltefosine (11,14) against promastigotes of these parasites, for this reason they were selected to determine their mechanism of action to know the cell death type.
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Experimental structure based drug design (SBDD) applications for anti-leishmanial drugs: A paradigm shift?
Miguel Marín,Marta López,Laura Gallego-Yerga,Raquel Álvarez,Rafael Peláez +4 more
- 24 Dec 2023
TL;DR: This work has revised the experimental structure-based drug design (SBDD) efforts applied to the discovery of new drugs against leishmaniasis and grouped the explored targets according to the metabolic pathways they belong to, and the key achieved advances are highlighted and evaluated.
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Structural Characterization of Human Heat Shock Protein 90 N-Terminal Domain and Its Variants K112R and K112A in Complex with a Potent 1,2,3-Triazole-Based Inhibitor
G. Tassone,Marco Mazzorana,Stefano Mangani,Elena Petricci,Elena Cini,Giuseppe Giannini,Cecilia Pozzi,Samuele Maramai +7 more
TL;DR: In this paper , a series of potent Hsp90 inhibitors based on a 1,4,5-trisubstituted 1,2,3-triazole scaffold was developed.
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References
Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays
TL;DR: A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation and is used to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
55.8K
Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization
Veit Hornung,Franz Bauernfeind,Annett Halle,Eivind O. Samstad,Eivind O. Samstad,Hajime Kono,Kenneth L. Rock,Katherine A. Fitzgerald,Eicke Latz,Eicke Latz +9 more
TL;DR: It is demonstrated that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3, which senses lysosomal damage as an endogenous 'danger' signal.
The re-emergence of natural products for drug discovery in the genomics era
TL;DR: This work reviews strategies for natural product screening that harness the recent technical advances that have reduced technical barriers and assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products.
HSP90 at the hub of protein homeostasis: emerging mechanistic insights
TL;DR: Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.
1.8K
Crystal structure of an Hsp90–nucleotide–p23/Sba1 closed chaperone complex
Maruf M.U. Ali,S. Mark Roe,Cara K. Vaughan,Phillipe Meyer,Phillipe Meyer,Barry Panaretou,Peter W. Piper,Chrisostomos Prodromou,Laurence H. Pearl +8 more
TL;DR: The structure reveals the complex architecture of the ‘closed’ state of the Hsp90 chaperone, the extensive interactions between domains and between protein chains, the detailed conformational changes in the amino-terminal domain that accompany ATP binding, and the structural basis for stabilization of the closed state by p23/Sba1.
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