Can the Plasmodium falciparum Nedd8 pathway provide new targets for malaria control?

恶性疟原虫 Nedd8 通路能否为疟疾控制提供新靶点？

• 批准号: BB/R001642/1
• 负责人: Katerina Artavanis-Tsakonas
• 金额: $ 57.04万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR001642%2F1
• 关键词: Plasmodium; falciparum; Nedd8; pathway; provide

Ubiquitin and Nedd8 are involved in fundamental cellular processes and are essential to all eukaryotes. As such, enzymes mediating their dynamic attachment and removal from substrates present attractive targets for therapeutic intervention for both chronic and communicable diseases. Despite being evolutionarily conserved, differences in how these pathways are controlled in higher and lower eukaryotes do exist and could potentially be exploited to generate pathogen-specific inhibitors. It is, therefore, necessary to understand the cell biological mechanisms behind how these pathways are regulated. We have evidence to support that removal of Nedd8 from target proteins in the malaria parasite, Plasmodium falciparum, is mediated by different enzymes than those of the human host. We now aim to characterize enzymes involved in Nedd8 attachment. We also aim to assess whether these enzymes are essential to P. falciparum survival and if they can be selectively disrupted in the parasite through peptide inhibitors. Overall, we hope to gain a better understanding of how the Nedd8 pathway has evolved across eukaryotes and identify patterns to predict its function in other parasites more widely.

泛素和Nedd8参与基本的细胞过程，是所有真核生物所必需的。因此，介导其动态附着和从底物去除的酶为慢性和传染性疾病的治疗干预提供了有吸引力的靶标。尽管在进化上是保守的，但这些途径在高等和低等真核生物中的控制方式确实存在差异，并且可能被利用来产生病原体特异性抑制剂。因此，有必要了解这些途径是如何调节的细胞生物学机制。我们有证据支持Nedd8从疟疾寄生虫（恶性疟原虫）的靶蛋白中去除是由与人类宿主不同的酶介导的。我们现在的目标是表征参与Nedd8附着的酶。我们还旨在评估这些酶是否是恶性疟原虫生存所必需的，以及它们是否可以通过肽抑制剂在寄生虫中被选择性地破坏。总的来说，我们希望更好地了解Nedd8通路如何在真核生物中进化，并确定模式以更广泛地预测其在其他寄生虫中的功能。

项目成果

Targeting the Plasmodium falciparum UCHL3 ubiquitin hydrolase using chemically constrained peptides

使用化学限制肽靶向恶性疟原虫 UCHL3 泛素水解酶

• DOI: 10.1101/2024.01.11.575158
• 发表时间: 2024
• 作者: King H

Nedd8 hydrolysis by UCH proteases in Plasmodium parasites

疟原虫寄生虫中 UCH 蛋白酶对 Nedd8 的水解

• DOI: 10.17863/cam.46680
• 发表时间: 2019
• 作者: Artavanis-Tsakonas K

Ubiquitin-Like Modifiers: Emerging Regulators of Protozoan Parasites.

• DOI: 10.3390/biom10101403
• 发表时间: 2020-10-03
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Karpiyevich M;Artavanis-Tsakonas K
• 通讯作者: Artavanis-Tsakonas K