Selection and Optimization of Hits from a High-Throughput Phenotypic Screen Against
            <i>Trypanosoma Cruzi</i>

Keenan, Martine; Alexander, Paul W.; Chaplin, Jason H.; Abbott, Michael J.; Diao, H.; Wang, Zhisen; Best, Wayne M.; Perez, Catherine; Cornwall, Scott; Keatley, Sarah; Thompson, R.C.A.; Charman, Susan A.; White, Karen L.; Ryan, Eileen; Chen, Gong; Ioset, Jean‐Robert; Geldern, Thomas W von; Chatelain, Eric

doi:10.4155/fmc.13.139

Cited by 19 publications

(14 citation statements)

References 41 publications

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“…More than a million compounds have been screened against T. cruzi and Leishmania spp. [54][55][56] , but the rate of hit discovery still lags far behind that for malaria. It remains necessary to avoid discarding precious chemical series by setting the hit…”

Section: Visceral Leishmaniasis and Chagas Diseasementioning

confidence: 96%

Hit and lead criteria in drug discovery for infectious diseases of the developing world

Katsuno

Burrows

Duncan

et al. 2015

Nat Rev Drug Discov

471

431

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Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.

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Section: Visceral Leishmaniasis and Chagas Diseasementioning

confidence: 96%

Hit and lead criteria in drug discovery for infectious diseases of the developing world

Katsuno

Burrows

Duncan

et al. 2015

Nat Rev Drug Discov

471

431

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“…At the end of the treatment, surviving animals from each group were euthanized, and blood and tissue samples were obtained for T. cruzi DNA detection by real-time PCR (qPCR) and histopathology. Remaining animals with undetectable parasitemia were left without treatment for days, with periodic checks for re-emergence of bloodstream parasites, and then subjected to a cyclophosphamide (CYP)-based immunosuppression protocol to rule out parasite reemergence from sanctuary sites in tissues [14]. Briefly, CYP was given once a…”

Section: Determination Of Parasitological Curementioning

confidence: 99%

Molecular and biological characterization of a highly pathogenic Trypanosoma cruzi strain isolated from a patient with congenital infection

Gulin

Bisio

Rocco

et al. 2018

Experimental Parasitology

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Although many Trypanosoma cruzi (T. cruzi) strains isolated from a wide range of hosts have been characterized, there is a lack of information about biological features from vertically transmitted strains. We describe the molecular and biological characteristics of the T. cruzi VD strain isolated from a congenital Chagas disease patient. The VD strain was typified as DTU TcVI; in vitro sensitivity to nifurtimox (NFX) and beznidazole (BZ) were 2.88 μM and 6.19 μM respectively, while inhibitory concentrations for intracellular amastigotes were 0.24 μM for BZ, and 0.66 μM for NFX. Biological behavior of VD strain was studied in a mouse model of acute infection, resulting in high levels of parasitemia and mortality with a rapid clearence of bloodstream trypomastigotes when treated with BZ or NFX, preventing mortality and reducing parasitic load and intensity of inflammatory infiltrate in skeletal and cardiac muscle. Treatment-induced parasitological cure, evaluated after immunossupression were 41% and 35% for BZ and NFX treatment respectively, suggesting a partial response to these drugs in elimination of parasite burden. This exhaustive characterization of this T. cruzi strain provides the basis for inclusion of this strain in a panel of reference strains for drug screening and adds a new valuable tool for the study of experimental T. cruzi infection.

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“…Recently developed and optimized lead compounds include the ergosterol biosynthesis inhibitors EPL-BS1937, EPL-BS2391, EPL-BS0967, and EPL-BS1246. All have recently been shown to be non-azole inhibitors of T. cruzi CYP51 (Hargrove et al., 2013, Keenan et al., 2013a, Keenan et al., 2013b). …”

Section: Introductionmentioning

confidence: 99%

In vitro drug susceptibility of two strains of the wildlife trypanosome, Trypanosoma copemani : A comparison with Trypanosoma cruzi

Botero

Keatley

Peacock

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Trypanosomes are blood protozoan parasites that are capable of producing illness in the vertebrate host. Within Australia, several native Trypanosoma species have been described infecting wildlife. However, only Trypanosoma copemani has been associated with pathological lesions in wildlife hosts and more recently has been associated with the drastic decline of the critically endangered woylie (Bettongia penicillata). The impact that some trypanosomes have on the health of the vertebrate host has led to the development of numerous drug compounds that could inhibit the growth or kill the parasite. This study investigated and compared the in vitro susceptibility of two strains of T. copemani (G1 and G2) and one strain of Trypanosoma cruzi (10R26) against drugs that are known to show trypanocidal activity (benznidazole, posaconazole, miltefosine and melarsoprol) and against four lead compounds, two fenarimols and two pyridine derivatives (EPL-BS1937, EPL-BS2391, EPL-BS0967, and EPL-BS1246), that have been developed primarily against T.cruzi. The in vitro cytotoxicity of all drugs against L6 rat myoblast cells was also assessed. Results showed that both strains of T. copemani were more susceptible to all drugs and lead compounds than T. cruzi, with all IC50 values in the low and sub-μM range for both species. Melarsoprol and miltefosine exhibited the highest drug activity against both T. copemani and T. cruzi, but they also showed the highest toxicity in L6 cells. Interestingly, both fenarimol and pyridine derivative compounds were more active against T. copemani and T. cruzi than the reference drugs benznidazole and posaconazole. T. copemani strains exhibited differences in susceptibility to all drugs demonstrating once again considerable differences in their biological behaviour.

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Selection and Optimization of Hits from a High-Throughput Phenotypic Screen Against Trypanosoma Cruzi

Abstract: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.

Cited by 19 publications

References 41 publications

Hit and lead criteria in drug discovery for infectious diseases of the developing world

Hit and lead criteria in drug discovery for infectious diseases of the developing world

Molecular and biological characterization of a highly pathogenic Trypanosoma cruzi strain isolated from a patient with congenital infection

In vitro drug susceptibility of two strains of the wildlife trypanosome, Trypanosoma copemani : A comparison with Trypanosoma cruzi

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