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Novel lead compounds in pre-clinical development against African sleeping sickness.

ABSTRACT: Human African trypanosomiasis (HAT), also known as African sleeping sickness, is caused by parasitic protozoa of the genus Trypanosoma. As the disease progresses, the parasites cross the blood brain barrier and are lethal for the patients if the disease is left untreated. Current therapies suffer from several drawbacks due to e.g. toxicity of the respective compounds or resistance to approved antitrypanosomal drugs. In this review, the different strategies of drug development against HAT are considered, namely the target-based approach, the phenotypic high throughput screening and the drug repurposing strategy. The most promising compounds emerging from these approaches entering an in vivo evaluation are mentioned herein. Of note, it may turn out to be difficult to confirm in vitro activity in an animal model of infection; however, possible reasons for the missing efficacy in unsuccessful in vivo studies are discussed.

SUBMITTER: Berninger M

PROVIDER: S-EPMC6072528 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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Novel lead compounds in pre-clinical development against African sleeping sickness.

Berninger Michael M Schmidt Ines I Ponte-Sucre Alicia A Holzgrabe Ulrike U

MedChemComm 20170731 10

Human African trypanosomiasis (HAT), also known as African sleeping sickness, is caused by parasitic protozoa of the genus <i>Trypanosoma</i>. As the disease progresses, the parasites cross the blood brain barrier and are lethal for the patients if the disease is left untreated. Current therapies suffer from several drawbacks due to <i>e.g.</i> toxicity of the respective compounds or resistance to approved antitrypanosomal drugs. In this review, the different strategies of drug development again ...[more]

PMID: 30108710

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Project description:The protozoan parasite Trypanosoma brucei is the causative agent of human African sleeping sickness and related animal diseases, and it has over 170 predicted protein kinases. Protein phosphorylation is a key regulatory mechanism for cellular function that, thus far, has been studied in T.brucei principally through putative kinase mRNA knockdown and observation of the resulting phenotype. However, despite the relatively large kinome of this organism and the demonstrated essentiality of several T. brucei kinases, very few specific phosphorylation sites have been determined in this organism. Using a gel-free, phosphopeptide enrichment-based proteomics approach we performed the first large scale phosphorylation site analyses for T.brucei. Serine, threonine, and tyrosine phosphorylation sites were determined for a cytosolic protein fraction of the bloodstream form of the parasite, resulting in the identification of 491 phosphoproteins based on the identification of 852 unique phosphopeptides and 1204 phosphorylation sites. The phosphoproteins detected in this study are predicted from their genome annotations to participate in a wide variety of biological processes, including signal transduction, processing of DNA and RNA, protein synthesis, and degradation and to a minor extent in metabolic pathways. The analysis of phosphopeptides and phosphorylation sites was facilitated by in-house developed software, and this automated approach was validated by manual annotation of spectra of the kinase subset of proteins. Analysis of the cytosolic bloodstream form T. brucei kinome revealed the presence of 44 phosphorylated protein kinases in our data set that could be classified into the major eukaryotic protein kinase groups by applying a multilevel hidden Markov model library of the kinase catalytic domain. Identification of the kinase phosphorylation sites showed conserved phosphorylation sequence motifs in several kinase activation segments, supporting the view that phosphorylation-based signaling is a general and fundamental regulatory process that extends to this highly divergent lower eukaryote.

Dataset Information

Novel lead compounds in pre-clinical development against African sleeping sickness.

Publications

Novel lead compounds in pre-clinical development against African sleeping sickness.

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