Screening and Identification of Inhibitors of <i>Trypanosoma brucei</i> Cathepsin L with Antitrypanosomal Activity

Jefferson, Tierra; McShan, Danielle; Warfield, Jasmine; Ogungbe, Ifedayo Victor

doi:10.1111/cbdd.12628

Cited by 14 publications

(10 citation statements)

References 11 publications

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“…Currently, the Malaria Box has been screened against a number of P. falciparum targets and multiple developmental stages (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), as well as other pathogens (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). These studies have identified compounds in the Malaria Box with efficacy against specific metabolic processes, such as the thioredoxin system (9), isoprenoid biosynthesis (14,30), and aminopeptidases (11), as well as protein translation (10) and beta-hematin formation (17).…”

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confidence: 99%

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Allman

Painter

Jasmeet

et al. 2016

Antimicrob Agents Chemother

130

196

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The threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective against Plasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated the in vitro metabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field.

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confidence: 99%

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Allman

Painter

Jasmeet

et al. 2016

Antimicrob Agents Chemother

130

196

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“…Furthermore, many other chemotypes have been identified as non-peptide rhodesain inhibitors, such as, thiosemicarbazones, isoquinolines, triazine nitriles, Michael acceptors 6 or recently reported non-covalent rhodesain inhibitors 7 . In this research area, our research group has been actively involved in the development of novel non-peptide 8 or peptidomimetic cysteine protease inhibitors 9,10 , the latter characterized by the presence of a 1,4-benzodiazepine scaffold, introduced into a peptide backbone, in which the condensed aromatic ring could mimic a Phe residue at P2 site, highly preferred by rhodesain, while the hydroxylmethyl group at C3 of the scaffold was used to tie different substituents, able to create additional interactions with the S3 pocket of the target enzyme.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors

Ettari

Previti

Cosconati

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Novel rhodesain inhibitors were developed by combining an enantiomerically pure 3-bromoisoxazoline warhead with a 1,4-benzodiazepine scaffold as specific recognition moiety. All compounds were proven to inhibit rhodesain with K i values in the low-micromolar range. Their activity towards rhodesain was found to be coupled to an in vitro antitrypanosomal activity, with IC 50 values ranging from the mid-micromolar to a low-micromolar value for the most active rhodesain inhibitor (R,S,S)-3. All compounds showed a good selectivity against the target enzyme since all of them were proven to be poor inhibitors of human cathepsin L.

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“…Proteases são enzimas que desempenham um papel vital no metabolismo, estando também envolvidas na infectividade, na diferenciação celular, na evasão da resposta imune e na patogenicidade dos tripanossomas (Garcia et al, 2011;Jefferson et al, 2016). Devido à grande diversidade, as proteases podem ser classificadas com base em dois critérios principais: tipo de reação catalisada e os mecanismos catalíticos envolvidos.…”

Section: Genes De Cisteína Proteases: Catepsina Lunclassified

Tripanossomas de ungulados no Brasil e na África: novas abordagens em estudos epidemiológicos de genótipos, vetores e reservatórios, e patologia de isolados Brasileiros.

Rodrigues¹

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também revelou todos os tripanossomas africanos patogênicos conhecidos para ungulados, incluindo T. suis recentemente redescoberto, em G. morsitans e G. pallidipes no PNG e RNN. As espécies mais prevalentes no intestino médio da mosca tsé-tsé foram T. congolense Savannah, seguido por T. simiae, T. simiae Tsavo, T. godfreyi e T. congolense Kilifi. Tsé-tsé de ambas as áreas também abrigavam Trypanozoon spp., T. suis (baixa prevalência) e T. vivax, que foi detectado, predominante, nas probóscides das moscas tsé-tsé. A diversidade de T. vivax descoberta por estudos anteriores no Leste da África têm sugerido um complexo de genótipos contrastantes com a alta homogeneidade de genótipos do Oeste da África e América do Sul. Neste estudo, utilizando o MDS (escalonamento multidimensional), análises filogenéticas de gGAPDH e genotipagem com sequências de ITS rDNA, nós caracterizamos T. vivax previamente identificado pelo FFLB em moscas tsé-tsé e em animais domésticos e selvagens de Moçambique, e comparamos com amostras de outros países do Oeste e Leste da África e América do Sul. Nossos resultados revelaram genótipos divergentes mais relacionados com T. vivax-like, corroborando o grande repertório genético no Leste da África e a reduzida diversidade de isolados no gado do Oeste da África e América do Sul. Mais estudos são necessários em áreas preservadas do Leste da África para verificar o papel de T. vivax-like na epidemiologia da AAT. As moscas tsé-tsé do PNG e RNN apresentaram infecção por T. suis (6%), como detectado por FFLB, e foram submetidos à análise de gGAPDH. Os resultados identificaram T. suis e T. suis-like formando um agrupamento monofilético, promovendo assim, pela primeira vez, esclarecimentos filogenéticos de que o subgênero Pycnomonas é um complexo de espécies e genótipos. T. suis-like identificados neste estudo são novas espécies encontradas em G. morsitans e G. pallidipes, e em ungulados selvagens (Cape búfalos e antílopes) e domésticos (bovinos e caprinos). Ao todo, os dados deste estudo amplamente contribuíram para a compreensão da epidemiologia, patologia, reservatórios, diversidade genética e história evolutiva de T. vivax na América do Sul e África. Além disso, a descoberta de novos genótipos e espécies relacionadas com T. vivax (subgênero Duttonella) e T. suis (Pycnomonas) e uma grande amostragem de espécies do subgênero Nannomonas identificados em Moçambique, provê novas linhas de investigação sobre a diversidade, patogenicidade, evolução e taxonomia de tripanossomas africanos.

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Screening and Identification of Inhibitors of Trypanosoma brucei Cathepsin L with Antitrypanosomal Activity

Cited by 14 publications

References 11 publications

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Synthesis and biological evaluation of novel peptidomimetics as rhodesain inhibitors

Tripanossomas de ungulados no Brasil e na África: novas abordagens em estudos epidemiológicos de genótipos, vetores e reservatórios, e patologia de isolados Brasileiros.

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