Abstract：
:Novel strategies to target Trypanosoma brucei, Trypanosoma cruzi and Leishmania are urgently needed to generate better and safer drugs against Human African Trypanosomiasis, Chagas disease and Leishmaniasis, respectively. Here, we investigated the feasibility of selectively targeting in trypanosomatids the ubiquitin E1 activating enzyme (UBA1), an essential eukaryotic protein required for protein ubiquitination. Trypanosomatids contain two UBA1 genes in contrast to mammals and yeast that only have one, and using T. brucei as a model system, we show that both are active in vitro. Surprisingly, neither protein is inhibited by TAK-243, a potent inhibitor of human UBA1. This resistance stems from differences with the human protein at key amino acids, which includes a residue termed the gatekeeper because its mutation in E1s leads to resistance to TAK-243 and related compounds. Importantly, our results predict that trypanosomatid selective UBA1 inhibition is feasible and suggest ways to design novel compounds to achieve this.
journal_name
Sci Repjournal_title
Scientific reportsauthors
Boer DR,Bijlmakers MJdoi
10.1038/s41598-019-52618-3subject
Has Abstractpub_date
2019-11-07 00:00:00pages
16195issue
1issn
2045-2322pii
10.1038/s41598-019-52618-3journal_volume
9pub_type
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pub_type： 杂志文章
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pub_type： 杂志文章
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pub_type： 杂志文章,随机对照试验
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pub_type： 杂志文章
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pub_type： 已发布勘误
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更新日期：2017-03-02 00:00:00
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pub_type： 杂志文章,meta分析
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