7 results on '"Paonessa G"'
Search Results
2. Optimization of 2-(1H-imidazo-2-yl)piperazines series of Trypanosoma brucei growth inhibitors as potential treatment for the second stage of HAT
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Nadia Gennari, Maria Vittoria Orsale, Vincenzo Summa, Rita Graziani, Simona Ponzi, Jesus Maria Ontoria Ontoria, Alina Ciammaichella, Steven J. Harper, Andreina Basta, Giacomo Paonessa, Ilaria Biancofiore, Valentina Nardi, Federica Ferrigno, Ivan Fini, Melania D'Amico, Ciammaichella, A., Ferrigno, F., Basta, A., D'Amico, M., Biancofiore, I., Nardi, V., Ponzi, S., Graziani, R., Gennari, N., Vittoria Orsale, M., Fini, I., Paonessa, G., Summa, V., Harper, S., and Ontoria, J. M.
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Antiparasitic ,Cell Survival ,medicine.drug_class ,Morpholines ,Trypanosoma brucei brucei ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Pharmacology ,Trypanosoma brucei ,01 natural sciences ,Biochemistry ,Piperazines ,Structure-Activity Relationship ,Isomerism ,In vivo ,Sleeping sickne ,Drug Discovery ,Human Umbilical Vein Endothelial Cells ,medicine ,Humans ,African trypanosomiasis ,Molecular Biology ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,medicine.disease ,biology.organism_classification ,Human African Trypanosomiasis (HAT) ,Trypanocidal Agents ,Growth Inhibitors ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Trypanosomiasis, African ,Quinolines ,Molecular Medicine - Abstract
A previous publication from our laboratory reported the identification of a new class of 2-(1H-imidazo-2-yl)piperazines as potent T. brucei growth inhibitors as potential treatment for Human African Trypanosomiasis (HAT). This work describes the structure–activity relationship (SAR) around the hit compound 1, which led to the identification of the optimized compound 18, a single digit nanomolar inhibitor (EC50 7 nM), not cytotoxic and with optimal in vivo profile that made it a suitable candidate for efficacy studies in a mouse model mimicking the second stage of disease.
- Published
- 2020
3. Discovery of 2-(1H-imidazo-2-yl)piperazines as a new class of potent and non-cytotoxic inhibitors of Trypanosoma brucei growth in vitro
- Author
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Annalise Di Marco, Steven J. Harper, Savina Malancona, Nadia Gennari, Simona Ponzi, Jesus Maria Ontoria Ontoria, Marcel Kaiser, Rita Graziani, Ilaria Biancofiore, Giacomo Paonessa, Alberto Bresciani, Federica Ferrigno, Vincenzo Summa, Ferrigno, F., Biancofiore, I., Malancona, S., Ponzi, S., Paonessa, G., Graziani, R., Bresciani, A., Gennari, N., Di Marco, A., Kaiser, M., Summa, V., Harper, S., and Ontoria, J. M.
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0301 basic medicine ,Antiparasitic ,medicine.drug_class ,030106 microbiology ,Clinical Biochemistry ,Plasmodium falciparum ,Trypanosoma brucei brucei ,Pharmaceutical Science ,Trypanosoma brucei ,HeLa Cell ,Biochemistry ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Sleeping sickne ,parasitic diseases ,Drug Discovery ,medicine ,Cytotoxic T cell ,Humans ,African trypanosomiasis ,Malaria, Falciparum ,Trypanosoma cruzi ,Molecular Biology ,Imidazole ,Piperazine ,biology ,2-(1H-imidazo-2-yl)piperazine ,Trypanocidal Agent ,Organic Chemistry ,Imidazoles ,Trypanosoma brucei rhodesiense ,medicine.disease ,biology.organism_classification ,Human African Trypanosomiasis (HAT) ,Virology ,Trypanocidal Agents ,030104 developmental biology ,Trypanosomiasis, African ,chemistry ,Molecular Medicine ,Growth inhibition ,Human ,HeLa Cells - Abstract
The identification of a new series of growth inhibitors of Trypanosoma brucei rhodesiense, causative agent of Human African Trypanosomiasis (HAT), is described. A selection of compounds from our in-house compound collection was screened in vitro against the parasite leading to the identification of compounds with nanomolar inhibition of T. brucei growth. Preliminary SAR on the hit compound led to the identification of compound 34 that shows low nanomolar parasite growth inhibition (T. brucei EC50 5 nM), is not cytotoxic (HeLa CC50 > 25,000 nM) and is selective over other parasites, such as Trypanosoma cruzi and Plasmodium falciparum (T. cruzi EC50 8120 nM, P. falciparum EC50 3624 nM).
- Published
- 2018
4. Discovery of a Selective Series of Inhibitors of Plasmodium falciparum HDACs
- Author
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Nadia Gennari, Emanuela Nizi, Steven J. Harper, Savina Malancona, Sergio Altamura, Edith Monteagudo, David Roberts, Ilaria Biancofiore, Paul Willis, Maria Vittoria Orsale, Ottavia Cecchetti, Antonella Cellucci, Ralph Laufer, Rita Graziani, Alberto Bresciani, Simona Ponzi, Jesus Maria Ontoria Ontoria, Maria Veneziano, Annalise Di Marco, Giacomo Paonessa, Vincenzo Summa, Federica Ferrigno, Ontoriajm, G Paonessa, G, Ponzi, S, Ferrigno, F, Nizi, E, Biancofiore, I, Malancona, S, Graziani, R, Roberts, D, Willis, P, Bresciani, A, Nadia Gennari, N, Cecchetti, O, Monteagudo, E, Orsale, Mv, Veneziano, M, Di Marco, A, Cellucci, A, Laufer, R, Sergio Altamura, S, Summa, V, and Harper, S
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0301 basic medicine ,biology ,Chemistry ,030106 microbiology ,Organic Chemistry ,Growth inhibitory ,Plasmodium falciparum ,biology.organism_classification ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,Mechanism of action ,Drug Discovery ,medicine ,medicine.symptom - Abstract
The identification of a new series of P. falciparum growth inhibitors is described. Starting from a series of known human class I HDAC inhibitors a SAR exploration based on growth inhibitory activity in parasite and human cells-based assays led to the identification of compounds with submicromolar inhibition of P. falciparum growth (EC50500 nM) and good selectivity over the activity of human HDAC in cells (up to50-fold). Inhibition of parasital HDACs as the mechanism of action of this new class of selective growth inhibitors is supported by hyperacetylation studies.
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- 2015
5. Production and structural characterization of amino terminally histidine tagged human oncostatin M in E. Coli
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Giampaolo Nitti, Pietro Pucci, Gaetano Barbato, Giacomo Paonessa, Elisabetta Sporeno, Rita Graziani, Sporeno, E, Barbato, G, Graziani, R, Pucci, Pietro, Nitti, G, and Paonessa, G.
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Peptide Biosynthesis ,Circular dichroism ,Transcription, Genetic ,Molecular Sequence Data ,Immunology ,Gene Expression ,Oncostatin M ,Spectrometry, Mass, Fast Atom Bombardment ,Polymerase Chain Reaction ,Biochemistry ,Protein Structure, Secondary ,Cell Line ,Complementary DNA ,Gene expression ,Escherichia coli ,Humans ,Immunology and Allergy ,Histidine ,Amino Acid Sequence ,Cloning, Molecular ,Molecular Biology ,Chromatography, High Pressure Liquid ,Helix bundle ,Expression vector ,Base Sequence ,biology ,Edman degradation ,Chemistry ,E. coli expression ,Hematology ,Molecular biology ,Growth Inhibitors ,Recombinant Proteins ,Models, Structural ,Histidine tag ,biology.protein ,Cytokines ,Tetradecanoylphorbol Acetate ,Peptides ,Circular dicroism - Abstract
Oncostatin M is a cytokine that acts as a growth regulator on a wide variety of cells and has diverse biological activities including acute phase protein induction, LDL receptor up-regulation and cell-specific gene expression. In order to gather information about the One M structure, we established a protocol for large scale production and single step purification of this functional cytokine from bacterial cells. The cDNA of human Onc M was cloned by RT-PCR from total RNA of PMA induced U937 cells. After the addition of a six histidine tag at the N-terminus, the coding region of mature Onc M was cloned in the pT7.7 expression vector. Histidine tagged Onc M was overexpressed in bacterial cells and purified to homogeneity in one step on a metal chelating column. We found that recombinant 6xHis-OncM remains fully active in a growth inhibition assay. Structural characterization of the purified protein was performed by electrospray mass spectrometry, automated Edman degradation and peptide mapping by high-pressure liquid chromatography/fast-atom-bombardment mass spectrometry. Thermal and pH stability dependence of Onc M was assessed by circular dichroism spectroscopy; the helical content is about 50%, in agreement with the four helix bundle fold postulated for cytokines that bind haematopoietic receptors of type I.
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- 1994
6. Transglutaminase-Mediated Modifications of the Rat Sperm Surface in Vitro
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P. Abrescia, S. Metafora, A. De Santis, G.F. Tajana, G Paonessa, Raffaele Porta, V. Gentile, Paonessa, G, Metafora, S, Tajana, G, Abrescia, P, DE SANTIS, A, Gentile, Vittorio, Porta, R., G., Paonessa, S., Metafora, G., Tajana, Abrescia, Paolo, A., DE SANTIS, V., Gentile, and Porta, Raffaele
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Male ,Spermidine ,Tissue transglutaminase ,Semen ,transglutaminase ,chemistry.chemical_compound ,sperm-coating antigen ,medicine ,Animals ,rat ,Epididymis ,Transglutaminases ,Multidisciplinary ,Spermatozoon ,biology ,urogenital system ,Spermatozoa ,Sperm ,Epithelium ,In vitro ,Rats ,medicine.anatomical_structure ,chemistry ,Biochemistry ,biology.protein ,Autoradiography ,Electrophoresis, Polyacrylamide Gel ,Acyltransferases - Abstract
Two transglutaminase-mediated modifications of the rat epididymal spermatozoon surface were demonstrated in vitro. Transglutaminase was effective in promoting the binding of spermidine to the sperm. Moreover, the enzyme, by reacting with one of the major proteins secreted by the rat seminal vesicle epithelium, produced a modified form of the protein with a higher molecular weight and the capability of binding to the sperm cells. A specific physiological role for the enzyme, bringing about modifications of the rat sperm surface in the seminal fluid environment, is suggested.
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- 1984
7. Specific recognition of cruciform DNA by nuclear protein HMG1
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Marco Bianchi, Monica Beltrame, Giacomo Paonessa, Bianchi, MARCO EMILIO, Beltrame, M, and Paonessa, G.
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Transcription, Genetic ,Immunoblotting ,Molecular Sequence Data ,Biology ,Genetic recombination ,DNA-binding protein ,chemistry.chemical_compound ,Animals ,Nuclear protein ,Cloning, Molecular ,Palindromic sequence ,Immunoassay ,Multidisciplinary ,Base Sequence ,Nucleic acid sequence ,High Mobility Group Proteins ,DNA ,Peptide Fragments ,Rats ,Molecular Weight ,Biochemistry ,chemistry ,Cruciform ,Liver ,Protein Biosynthesis ,DNA supercoil ,Nucleic Acid Conformation ,Electrophoresis, Polyacrylamide Gel - Abstract
Cruciform DNA, a non-double helix form of DNA, can be generated as an intermediate in genetic recombination as well as from palindromic sequences under the effect of supercoiling. Eukaryotic cells are equipped with a DNA-binding protein that selectively recognizes cruciform DNA. Biochemical and immunological data showed that this protein is HMG1, an evolutionarily conserved, essential, and abundant component of the nucleus. The interaction with a ubiquitous protein points to a critical role for cruciform DNA conformations.
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