| Item type |
文献 / Documents(1) |
| 公開日 |
2024-01-01 |
| アクセス権 |
|
|
アクセス権 |
open access |
|
アクセス権URI |
http://purl.org/coar/access_right/c_abf2 |
| 資源タイプ |
|
|
資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| 出版社版DOI |
|
|
|
関連識別子 |
https://doi.org/10.1371/journal.pntd.0000659 |
|
|
関連名称 |
10.1371/journal.pntd.0000659 |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
|
|
タイトル |
A Target-Based High Throughput Screen Yields Trypanosoma brucei Hexokinase Small Molecule Inhibitors with Antiparasitic Activity |
| 著者 |
Sharlow, Elizabeth R.
Lyda, Todd A.
Dodson, Heidi C.
Mustata, Gabriela
Morris, Meredith T.
Leimgruber, Stephanie S.
Lee, Kuo-Hsiung
柏田, 良樹
Close, David
Lazo, John S.
Morris, James C.
|
| 抄録 |
|
|
内容記述 |
Background: The parasitic protozoan Trypanosoma brucei utilizes glycolysis exclusively for ATP production during infection of the mammalian host. The first step in this metabolic pathway is mediated by hexokinase (TbHK), an enzyme essential to the parasite that transfers the γ-phospho of ATP to a hexose. Here we describe the identification and confirmation of novel small molecule inhibitors of bacterially expressed TbHK1, one of two TbHKs expressed by T. brucei, using a high throughput screening assay.
Methodology/Principal Findings: Exploiting optimized high throughput screening assay procedures, we interrogated 220,233 unique compounds and identified 239 active compounds from which ten small molecules were further characterized. Computation chemical cluster analyses indicated that six compounds were structurally related while the remaining four compounds were classified as unrelated or singletons. All ten compounds were ∼20-17,000-fold more potent than lonidamine, a previously identified TbHK1 inhibitor. Seven compounds inhibited T. brucei blood stage form parasite growth (0.03≤EC50<3 µM) with parasite specificity of the compounds being demonstrated using insect stage T. brucei parasites, Leishmania promastigotes, and mammalian cell lines. Analysis of two structurally related compounds, ebselen and SID 17387000, revealed that both were mixed inhibitors of TbHK1 with respect to ATP. Additionally, both compounds inhibited parasite lysate-derived HK activity. None of the compounds displayed structural similarity to known hexokinase inhibitors or human African trypanosomiasis therapeutics.
Conclusions/Significance: The novel chemotypes identified here could represent leads for future therapeutic development against the African trypanosome. |
| 書誌情報 |
en : PLoS Neglected Tropical Diseases
巻 4,
号 4,
p. e659,
発行日 2010-04-13
|
| 収録物ID |
|
|
収録物識別子タイプ |
EISSN |
|
収録物識別子 |
19352735 |
| 収録物ID |
|
|
収録物識別子タイプ |
PISSN |
|
収録物識別子 |
19352727 |
| 出版者 |
|
|
出版者 |
PLOS |
| 権利情報 |
|
|
権利情報 |
© 2010 Sharlow et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| EID |
|
|
識別子 |
235907 |
| 言語 |
|
|
言語 |
eng |
pntd_4_4_e659.pdf (285 KB)
.png)
