Publications by authors named "Francesco Di Chiaro"

2 Publications

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Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking.

Sci Rep 2015 May 7;5:9705. Epub 2015 May 7.

1] European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100, Siena [2] Dip. di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.

Leishmaniasis is a neglected vector-born disease caused by a protozoan of the genus Leishmania and affecting more than 1.300.000 people worldwide. The couple tryparedoxin/tryparedoxin peroxidase is essential for parasite survival in the host since it neutralizes the hydrogen peroxide produced by macrophages during the infection. Herein we report a study aimed at discovering the first class of compounds able to non-covalently inhibit tryparedoxin peroxidase. We have solved the high-resolution structure of Tryparedoxin peroxidase I from Leishmania major (LmTXNPx) in the reduced state and in fully folded conformation. A first series of compounds able to inhibit LmTXNPx was identified by means of the high throughput docking technique. The inhibitory activity of these compounds was validated by a Horseradish peroxidase-based enzymatic assay and their affinity for LmTXNPx calculated by surface plasmon resonance experiments. On the basis of these results, the analysis of the enzyme-inhibitor docked models allowed us to rationally design and synthesize a series of N,N-disubstituted 3-aminomethyl quinolones. These compounds showed an inhibitory potency against LmTXNPx in the micromolar range. Among them, compound 12 represents the first non-covalent LmTXNPx inhibitor reported to date and could pave the way to the discovery of a new class of drugs against leishmaniasis.
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http://dx.doi.org/10.1038/srep09705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423475PMC
May 2015

Structural insights into the enzymes of the trypanothione pathway: targets for antileishmaniasis drugs.

Future Med Chem 2013 Oct;5(15):1861-75

National Research Council of Italy, Institute of Molecular Biology & Pathology, Rome, Italy c/o Department of Biochemical Sciences 'A. Rossi Fanelli', University Sapienza, Rome, Italy.

Leishmaniasis is a neglected disease that kills 60,000 people worldwide, and which is caused by the protozoa Leishmania. The enzymes of the trypanothione pathway: trypanothione synthetase-amidase, trypanothione reductase (TR) and tryparedoxin-dependent peroxidase are absent in human hosts, and are essential for parasite survival and druggable. The most promising target is trypanothione synthetase-amidase, which has been also chemically validated. However, the structural data presented in this review show that TR also should be considered as a good target. Indeed, it is strongly inhibited by silver- and gold-containing compounds, which are active against Leishmania parasites and can be used for the development of novel antileishmanial agents. Moreover, TR trypanothione-binding site is not featureless but contains a sub-pocket where inhibitors bind, potentially useful for the design of new lead compounds.
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http://dx.doi.org/10.4155/fmc.13.146DOI Listing
October 2013