Journal ArticleDOI
Development of rhodesain inhibitors with a 3-bromoisoxazoline warhead.
Roberta Ettari,Lucia Tamborini,Ilenia C. Angelo,Silvana Grasso,Tanja Schirmeister,Leonardo Lo Presti,Carlo De Micheli,Andrea Pinto,Paola Conti +8 more
TLDR
Novel rhodesain inhibitors were obtained by combining an enantiomerically pure 3‐bromoisoxazoline warhead with a specific peptidomimetic recognition moiety, and a preference for parasitic over human proteases, specifically cathepsins B and L, was observed.Abstract:
Novel rhodesain inhibitors were obtained by combining an enantiomerically pure 3-bromoisoxazoline warhead with a specific peptidomimetic recognition moiety. All derivatives behaved as inhibitors of rhodesain, with low micromolar Ki values. Their activity against the enzyme was found to be paralleled by an in vitro antitrypanosomal activity, with IC50 values in the mid-micromolar range. Notably, a preference for parasitic over human proteases, specifically cathepsins B and L, was observed.read more
Citations
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Development of Novel Peptide-Based Michael Acceptors Targeting Rhodesain and Falcipain-2 for the Treatment of Neglected Tropical Diseases (NTDs)
Santo Previti,Roberta Ettari,Sandro Cosconati,Giorgio Amendola,Khawla Chouchene,Annika Wagner,Annika Wagner,Ute A. Hellmich,Ute A. Hellmich,Kathrin Ulrich,R. Luise Krauth-Siegel,Peter Wich,Ira Schmid,Tanja Schirmeister,Jiri Gut,Philip J. Rosenthal,Silvana Grasso,Maria Zappalà +17 more
TL;DR: A class of peptide-based inhibitors based on a characteristic peptide sequence for the inhibition of the cysteine proteases rhodesain of Trypanosoma brucei rhodesiense and falcipain-2 of Plasmodiumfalciparum are developed as novel antitrypanosomal and antimalarial agents.
Journal ArticleDOI
Discovery of Covalent Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase, A Target for the Treatment of Malaria
Stefano Bruno,Andrea Pinto,Gianluca Paredi,Lucia Tamborini,Carlo De Micheli,Valeria La Pietra,Luciana Marinelli,Ettore Novellino,Paola Conti,Andrea Mozzarelli +9 more
TL;DR: A new class of covalent inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate dehydrogenase is developed by screening a small library of 3-bromo-isoxazoline derivatives that inactivate the enzyme through a covalents, selective bond to the catalytic cysteine, as demonstrated by mass spectrometry.
Journal ArticleDOI
Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation
Roberta Ettari,Andrea Pinto,Santo Previti,Lucia Tamborini,Ilenia C. Angelo,Valeria La Pietra,Luciana Marinelli,Ettore Novellino,Tanja Schirmeister,Maria Zappalà,Silvana Grasso,Carlo De Micheli,Paola Conti +12 more
TL;DR: Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent.
Journal ArticleDOI
Optimization of peptidomimetic boronates bearing a P3 bicyclic scaffold as proteasome inhibitors.
Valeria Troiano,Kety Scarbaci,Roberta Ettari,Nicola Micale,Carmen Cerchia,Andrea Pinto,Tanja Schirmeister,Ettore Novellino,Silvana Grasso,Antonio Lavecchia,Maria Zappalà +10 more
TL;DR: A new series of pseudopeptide boronate proteasome inhibitors bearing a bicyclic 1,6-naphthyridin-5(6H)-one scaffold as P3 fragment emerged as promising lead compound for the development of anticancer agents targeting melanoma and non-small cell lung cancer.
Journal ArticleDOI
Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors
Roberta Ettari,Santo Previti,Sandro Cosconati,Jochen Kesselring,Tanja Schirmeister,Silvana Grasso,Maria Zappalà +6 more
TL;DR: Novel rhodesain inhibitors were developed by combining an enantiomerically pure 3-bromoisoxazoline warhead with a 1,4-benzodiazepine scaffold as specific recognition moiety with good selectivity against the target enzyme since all of them were proven to be poor inhibitors of human cathepsin L.
References
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A short history of SHELX
TL;DR: This paper could serve as a general literature citation when one or more of the open-source SH ELX programs (and the Bruker AXS version SHELXTL) are employed in the course of a crystal-structure determination.
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Human malaria parasites in continuous culture
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The Alamar Blue® assay to determine drug sensitivity of African trypanosomes (T.b. rhodesiense and T.b. gambiense) in vitro
TL;DR: The Alamar Blue assay can be applied for drug screening, since it is simple, reproducible and economical, and can also be used in field sites with less equipped laboratories, because in addition to fluorometric endpoint determination, a colorimetric reading is possible.
Journal ArticleDOI
Cultivation in a semi-defined medium of animal infective forms of Trypanosoma brucei, T. equiperdum, T. evansi, T. rhodesiense and T. gambiense.
TL;DR: The cultured trypanosomes had all the characteristics of the in vivo bloodstream forms including: morphology, infectivity, antigenic variation and glucose metabolism.