scholarly journals Μελέτη μορίων που παίζουν σημαντικό ρόλο στην ανάπτυξη των πρωτόζωων Leishmania και Trypanosoma

2014 ◽  
Author(s):  
Αντωνία Ευσταθίου
Keyword(s):  
Trypanosoma Cruzi ◽  
Trypanosoma Brucei ◽  
Leishmania Spp

Τα πρωτόζωα Leishmania spp., Trypanosoma brucei και Trypanosoma cruzi ανήκουν στις τρυπανοσωματίδες και είναι παράσιτα που προκαλούν τις ασθένειες λεϊσμανίαση, Ανθρώπινη Αφρικανική Τρυπανοσωμίαση (ΗΑΤ) και Αμερικανική Τρυπανοσωμίαση (Νόσος του Chagas), αντίστοιχα. Αυτές οι παραμελημένες ασθένειες προκαλούν σημαντική νοσηρότητα και υψηλά ποσοστά θνησιμότητας παγκοσμίως. Μέχρι σήμερα, δεν έχουν ανακαλυφθεί αποτελεσματικά εμβόλια για τον άνθρωπο για την πρόληψη των ασθενειών αυτών, ενώ η χημειοθεραπεία είναι συχνά αναποτελεσματική ή/και τοξική και έχει υψηλό κόστος. Για το λόγο αυτό, είναι επιτακτική ανάγκη εύρεσης καινούριων και ιδανικότερα στοχευμένων χημειοθεραπειών. Παράλληλα, η αναζήτηση ιδανικών υποψήφιων παρασιτικών παραγόντων όπου η στόχευση τους να αναστέλλει επιλεκτικά τη διαφοροποίηση και ανάπτυξη των τρυπανοσωματίδων είναι μείζονος σημασίας. Τα παραπάνω αναμένεται να οδηγήσουν στον ορθολογικό σχεδιασμό καινούριων φαρμάκων. Η ολοκλήρωση της χαρτογράφησης του γονιδιώματος πολλών ειδών των τρυπανοσωματίδων μας παρέχει πλούτο γνώσης που μπορεί να χρησιμοποιηθεί για την αναγνώριση των ιδανικών στόχων και των αντίστοιχων υποψήφιων φαρμάκων. Τα φάρμακα αυτά στη συνέχεια πρέπει να επιλεχθούν έτσι ώστε να εμφανίζουν επιλεκτικότητα έναντι των παρασιτικών πρωτεϊνών αντί των πρωτεϊνών του θηλαστικού ξενιστή. Στην παρούσα διατριβή, επικεντρωθήκαμε στη μελέτη σημαντικών πρωτεϊνών των παρασίτων, και μοριακών στόχων φαρμάκων για τη θεραπεία της λεϊσμανίασης και της ΗΑΤ, που παίζουν σημαντικό ρόλο στην εξέλιξη του κυτταρικού κύκλου και στη βιωσιμότητα του παρασίτου. Πιο συγκεκριμένα, επικεντρωθήκαμε στην μελέτη της κινάσης της συνθετάσης του γλυκογόνου 3 (GSK-3) και της cdc2-σχετιζόμενης κινάσης 3 (CRK3). Μια βιβλιοθήκη χημικών αναστολέων που απαρτίζεται από ανάλογα ιντιρουμπίνης (μια δις-ινδόλη που απαντάται σε μαλάκια και φυτά), τα οποία στοχεύουν τις αντίστοιχες κινάσες των θηλαστικών δρώντας ως ATP-ανταγωνιστικοί αναστολείς, βρέθηκε να έχουν ισχυρή αντιπαρασιτική δράση. Ο τρόπος δράσης των αναλόγων αυτών υποδηλώνει σημαντικές διαφορές στο ενεργό κέντρο της κινάσης GSK-3 των παρασίτων Leishmania και Τ. brucei, αλλά και σε σχέση με την ομόλογη ανθρώπινη GSK-3. Ταυτόχρονα, οι αναστολείς αυτοί δοκιμάστηκαν για την δράση τους έναντι των παρασίτων Τ. cruzi τόσο in vitro όσο και in vivo. Τέλος, ένας αναστολέας βρέθηκε να είναι πολλά υποσχόμενος έναντι της νόσου του Chagas σε ποντικούς Balb/c ενώ δύο αναστολείς της λεϊσμανιακής GSK-3 βρέθηκαν να έχουν υποσχόμενη δραστικότητα στην οξεία και στη χρόνια φάση της σπλαχνικής λεϊσμανίασης σε πειραματικό μοντέλο ποντικού Balb/C. Η περαιτέρω μελέτη της in vivo δράσης των αναστολέων αυτών μπορεί να βοηθήσει στην διαλεύκανση του μηχανισμού δράσης των αναστολέων της GKS-3 ή/και να χρησιμεύσει στην ανάπτυξη μιας συνδυαστικής θεραπείας εναντίον της λεϊσμανίασης και της αμερικάνικής τρυπανοσωμίασης. Συνοπτικά, τα αποτελέσματα που περιγράφονται παραπάνω συμβάλλουν στην ανάπτυξη ανακάλυψης στοχευμένων φαρμάκων έναντι των παρασιτικών κινασών για τη θεραπεία της λεϊσμανίασης, της ΗΑΤ και της νόσου του Chagas.

Activity of a hydroxybibenzyl bryophyte constituent against Leishmania spp. and Trypanosoma cruzi: In silico, in vitro and in vivo activity studies

2008 ◽  
Vol 43 (9) ◽  
pp. 1797-1807 ◽  
Author(s):  
Virginia Roldos ◽  
Hector Nakayama ◽  
Miriam Rolón ◽  
Alina Montero-Torres ◽  
Fernando Trucco ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
In Silico ◽  
Leishmania Spp

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

Naphthoquinones and derivatives for chemotherapy: perspectives and limitations of their anti-trypanosomatids activities

2020 ◽  
Vol 26 ◽  
Author(s):  
Luíza Dantas-Pereira ◽  
Edézio F. Cunha-Junior ◽  
Valter V. Andrade-Neto ◽  
John F. Bower ◽  
Guilherme A. M. Jardim ◽  
...  
Keyword(s):  
Large Scale ◽  
Neglected Tropical Diseases ◽  
Folk Medicine ◽  
Leishmania Species ◽  
Parasitic Infections ◽  
Mechanistic Analysis ◽  
Leishmania Spp ◽  
Nanomolar Range

: Chagas disease, Sleeping sickness and Leishmaniasis, caused by trypanosomatids Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively, are considered neglected tropical diseases, and they especially affect impoverished populations in the developing world. The available chemotherapies are very limited and a search for alternatives is still necessary. In folk medicine, natural naphthoquinones have been employed for the treatment of a great variety of illnesses, including parasitic infections. This review is focused on the anti-trypanosomatid activity and mechanistic analysis of naphthoquinones and derivatives. Among all the series of derivatives tested in vitro, naphthoquinone-derived 1,2,3-triazoles were very active on T. cruzi infective forms in blood bank conditions, as well as in amastigotes of Leishmania spp. naphthoquinones containing a CF3 on a phenyl amine ring inhibited T. brucei proliferation in the nanomolar range, and naphthopterocarpanquinones stood out for their activity on a range of Leishmania species. Some of these compounds showed a promising selectivity index (SI) (30 to 1900), supporting further analysis in animal models. Indeed, high toxicity to the host and inactivation by blood components are crucial obstacles to be overcome to use naphthoquinones and/or their derivatives for chemotherapy. Multidisciplinary initiatives embracing medicinal chemistry, bioinformatics, biochemistry, and molecular and cellular biology need to be encouraged to allow the optimization of these compounds. Large scale automated tests are pivotal for the efficiency of the screening step, and subsequent evaluation of both the mechanism of action in vitro and pharmacokinetics in vivo are essential for the development of a novel, specific and safe derivative, minimizing adverse effects.

scholarly journals Antitrypanosomal activity of purine nucleosides can be enhanced by their conversion to O-acetylated derivatives.

1996 ◽  
Vol 40 (11) ◽  
pp. 2567-2572 ◽  
Author(s):  
J R Sufrin ◽  
D Rattendi ◽  
A J Spiess ◽  
S Lane ◽  
C J Marasco ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Parent Compound ◽  
Nucleoside Analogs ◽  
Significant Activity ◽  
Structural Class ◽  
Antitrypanosomal Activity ◽  
Salvage Pathways ◽  
Purine Salvage Pathways

Fifteen purine nucleosides and their O-acetylated ester derivatives were examined for in vitro antitrypanosomal activity against the LAB 110 EATRO isolate of Trypanosoma brucei brucei and two clinical isolates of Trypanosoma brucei rhodesiense. Initial comparisons of activity were made for the LAB 110 EATRO isolate. Three nucleoside analogs exhibited no significant activity (50% inhibitory concentrations [IC50s] of > 100 microM), whether they were O acetylated or unacetylated; three nucleosides showed almost equal activity (IC50s of < 5 microM) for the parent compound and the O-acetylated derivative; nine nucleosides showed significantly improved activity (> or = 3-fold) upon O acetylation; of these nine analogs, six displayed activity at least 10-fold greater than that of their parent nucleosides. The most significant results were those for four apparently inactive compounds which, upon O acetylation, displayed IC50s of < or = 25 microM. When the series of compounds was tested against T. brucei rhodesiense isolates (KETRI 243 and KETRI 269), their antitrypanosomal effects were comparable to those observed for the EATRO 110 strain. Thus, our studies of purine nucleosides have determined that O acetylation consistently improved their in vitro antitrypanosomal activity. This observed phenomenon was independent of their cellular enzyme targets (i.e., S-adenosylmethionine, polyamine, or purine salvage pathways). On the basis of our results, the routine preparation of O-acetylated purine nucleosides for in vitro screening of antitrypanosomal activity is recommended, since O acetylation transformed several inactive nucleosides into compounds with significant activity, presumably by improving uptake characteristics. O-acetylated purine nucleosides may offer in vivo therapeutic advantages compared with their parent nucleosides, and this possibility should be considered in future evaluations of this structural class of trypanocides.

scholarly journals Characterization and selective inhibition of myristoyl-CoA:protein N-myristoyltransferase from Trypanosoma brucei and Leishmania major

2006 ◽  
Vol 396 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Chrysoula Panethymitaki ◽  
Paul W. Bowyer ◽  
Helen P. Price ◽  
Robin J. Leatherbarrow ◽  
Katherine A. Brown ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Leishmania Major ◽  
Homo Sapiens ◽  
Selective Inhibition ◽  
Fungal Species ◽  
Chemotherapeutic Agents ◽  
Human Pathogens ◽  
Ic50 Values

The eukaryotic enzyme NMT (myristoyl-CoA:protein N-myristoyltransferase) has been characterized in a range of species from Saccharomyces cerevisiae to Homo sapiens. NMT is essential for viability in a number of human pathogens, including the fungi Candida albicans and Cryptococcus neoformans, and the parasitic protozoa Leishmania major and Trypanosoma brucei. We have purified the Leishmania and T. brucei NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and specific peptide substrates. A number of inhibitory compounds that target NMT in fungal species have been tested against the parasite enzymes in vitro and against live parasites in vivo. Two of these compounds inhibit TbNMT with IC50 values of <1 μM and are also active against mammalian parasite stages, with ED50 (the effective dose that allows 50% cell growth) values of 16–66 μM and low toxicity to murine macrophages. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against infectious diseases including African sleeping sickness and Nagana.

scholarly journals Neurotrophin Receptor TrkC Is an Entry Receptor for Trypanosoma cruzi in Neural, Glial, and Epithelial Cells

2011 ◽  
Vol 79 (10) ◽  
pp. 4081-4087 ◽  
Author(s):  
Craig Weinkauf ◽  
Ryan Salvador ◽  
Mercio PereiraPerrin
Keyword(s):  
Trypanosoma Cruzi ◽  
Chagas Disease ◽  
Mammalian Cells ◽  
Chinese Hamster ◽  
Neuronal Cell ◽  
Host Cells ◽  
Neurotrophin Receptor ◽  
Content Type

ABSTRACTTrypanosoma cruzi, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated byT. cruzisurfacetrans-sialidase, also known as parasite-derived neurotrophic factor (PDNF). However, it has remained unclear whether TrkC is used byT. cruzito enter host cells. Here, we show that a neuronal cell line (PC12-NNR5) relatively resistant toT. cruzibecame highly susceptible to infection when overexpressing human TrkC but not human TrkB. Furthermore,trkCtransfection conferred an ∼3.0-fold intracellular growth advantage. Sialylation-deficient Chinese hamster ovarian (CHO) epithelial cell lines Lec1 and Lec2 also became much more permissive toT. cruziafter transfection with thetrkCgene. Additionally, NT-3 specifically blockedT. cruziinfection of the TrkC-NNR5 transfectants and of naturally permissive TrkC-bearing Schwann cells and astrocytes, as did recombinant PDNF. Two specific inhibitors of Trk autophosphorylation (K252a and AG879) and inhibitors of Trk-induced MAPK/Erk (U0126) and Akt kinase (LY294002) signaling, but not an inhibitor of insulin-like growth factor 1 receptor, abrogated TrkC-mediated cell invasion. Antibody to TrkC blockedT. cruziinfection of the TrkC-NNR5 transfectants and of cells that naturally express TrkC. The TrkC antibody also significantly and specifically reduced cutaneous infection in a mouse model of acute Chagas' disease. TrkC is ubiquitously expressed in the peripheral and central nervous systems, and in nonneural cells infected byT. cruzi, including cardiac and gastrointestinal muscle cells. Thus, TrkC is implicated as a functional PDNF receptor in cell entry, independently of sialic acid recognition, mediating broadT. cruziinfection bothin vitroandin vivo.

scholarly journals Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis

2010 ◽  
Vol 54 (7) ◽  
pp. 2893-2900 ◽  
Author(s):  
Antoaneta Y. Sokolova ◽  
Susan Wyllie ◽  
Stephen Patterson ◽  
Sandra L. Oza ◽  
Kevin D. Read ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
Human African Trypanosomiasis ◽  
Parent Drug ◽  
Cross Resistance ◽  
Pharmacokinetic Studies ◽  
African Trypanosomiasis ◽  
Trypanosoma Brucei Brucei ◽  
Resistant Lines

ABSTRACT The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (∼27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.

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