Plasmepsin X function in Plasmodium

Plasmodium 中 Plasmepsin X 的功能

• 批准号: 10322714
• 负责人: Daniel E. Goldberg
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-02 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322714
• 关键词: Address; Africa South of the Sahara; Antimalarials; Aspartic Endopeptidases; Back; Binding; Biochemical; Biological Assay; Biology; Biotinylation; Child; Cysteine; Data; Disease; Drug Kinetics; Enzymes; Erythrocytes; Event; Immunoprecipitation; Impairment; In Vitro; Invaded; Label; Lead; Malaria; Mass Spectrum Analysis; Modeling; Mutate; Oral; Organelles; Parasites; Pathogenesis; Peptide Hydrolases; Persons; Phenocopy; Physiologic pulse; Plasmodium; Process; Property; Protease Inhibitor; Proteins; Proteolysis; Proteomics; Random Peptide Libraries; Recombinants; Rodent; Secretory Vesicles; Serine Protease; Site; Specificity; Substrate Specificity; Synthetic Peptide Libraries; Time; asexual; drug development; inhibitor; insight; interest; knock-down; mutant; new therapeutic target; novel; novel therapeutics; plasmepsin; prevent

PROJECT SUMMARY / ABSTRACT Malaria afflicts several hundred million and kills more than 600,000 people each year, mostly children in Sub-Saharan Africa. Aspartic proteases have long been antimalarial targets of interest. A large number of aspartic protease inhibitors that are potent against parasites in culture have been developed, but their specific targets have been elusive. Plasmepsin X (PMX) is one of the least characterized aspartic proteases found in asexual intraerythrocytic malaria parasites. We have recently found that PMX is a key enzyme for intraerythrocytic parasite egress and invasion. It activates the master trigger subtilysin-like protease 1 (SUB1), launching proteolytic events that allow merozoites to get out of the host red blood cell (RBC) and invade fresh RBCs. We have identified a class of aspartic protease inhibitors called aminohydantoins that appear to kill parasites through PMX blockade, preventing SUB1 activation and impairing egress/invasion. PMX knockdown phenocopies inhibitor action. One of the inhibitors has favorable pharmacokinetic properties and gives oral cure in a rodent malaria model. We believe that PMX is an exciting new drug target but need to better characterize its function to inform ongoing drug development and enhance our understanding of parasite biology. To address these questions, aim 1 will examine the specificity of PMX and will address the question of whether SUB1 maturation by PMX is direct. Biochemical assays using isolated PMX with SUB1 as a substrate and with a random peptide library will be performed. Aim 2 will focus on what PMX interacts with. Is SUB1 the only substrate? What else is in the secretory vesicle called the exoneme, where PMX and SUB1 both reside? Aim 3 will address the question of how PMX itself gets activated. Our preliminary data suggest that there must be an upstream enzyme. We will characterize the processing and look for a maturase. We anticipate that the proposed studies will yield great insight into the pathogenesis of malaria and will point the way to new therapies for this devastating disease.

项目摘要/摘要

项目成果

Maturation and substrate processing topography of the Plasmodium falciparum invasion/egress protease plasmepsin X.

• DOI: 10.1038/s41467-022-32271-7
• 发表时间: 2022-08-04
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Mukherjee, Sumit;Nguyen, Suong;Sharma, Eashan;Goldberg, Daniel E.
• 通讯作者: Goldberg, Daniel E.

Activation of the Plasmodium Egress Effector Subtilisin-Like Protease 1 Is Mediated by Plasmepsin X Destruction of the Prodomain.

• DOI: 10.1128/mbio.00673-23
• 发表时间: 2023-04-25
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Mukherjee, Sumit;Nasamu, Armiyaw S.;Rubiano, Kelly C.;Goldberg, Daniel E.
• 通讯作者: Goldberg, Daniel E.

Rounding precedes rupture and breakdown of vacuolar membranes minutes before malaria parasite egress from erythrocytes.

• DOI: 10.1111/cmi.12868
• 发表时间: 2018-10
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Glushakova S;Beck JR;Garten M;Busse BL;Nasamu AS;Tenkova-Heuser T;Heuser J;Goldberg DE;Zimmerberg J
• 通讯作者: Zimmerberg J

Fast-Acting Small Molecules Targeting Malarial Aspartyl Proteases, Plasmepsins, Inhibit Malaria Infection at Multiple Life Stages.

针对疟疾天冬氨酰蛋白酶、纤溶酶的速效小分子可抑制多个生命阶段的疟疾感染。

• DOI: 10.1021/acsinfecdis.8b00197
• 发表时间: 2019
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Singh,Snigdha;Rajendran,Vinoth;He,Jiang;Singh,AmitK;Achieng,AngelaO;Vandana;Pant,Akansha;Nasamu,ArmiyawS;Pandit,Mansi;Singh,Jyoti;Quadiri,Afshana;Gupta,Nikesh;Poonam;Ghosh,PrahladC;Singh,BrajendraK;Narayanan,Latha;Kempai
• 通讯作者: Kempai