更新于：2024-11-01

PfACS

更新于：2024-11-01

基本信息

别名-

简介-

关联

项与 PfACS 相关的药物

MMV693183

靶点

PfACS

作用机制

PfACS抑制剂

在研机构

TropIQ Health Sciences BV

原研机构

TropIQ Health Sciences BV

在研适应症

疟疾

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PfACS 相关的临床结果

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100 项与 PfACS 相关的转化医学

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0 项与 PfACS 相关的专利（医药）

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项与 PfACS 相关的文献（医药）

2024-06-14·ACS Infectious Diseases

Understanding the Antiplasmodial Action of Resistance-Refractory Xanthoquinodin A1

Article

作者: Chang, Maya ; Jeon, Jin ; Chakrabarti, Debopam ; Wendt, Karen ; Nardella, Flore ; Cichewicz, Robert H ; Schaefer, Samuel ; Paes, Raphaella ; Jiang, Tiantian ; Santos, Natalia Mojica ; Collins, Jennifer E ; Rocamora, Frances ; Winzeler, Elizabeth A ; Lee, Jin Woo

Our previous work identified a series of 12 xanthoquinodin analogues and 2 emodin-dianthrones with broad-spectrum activities against Trichomonas vaginalis, Mycoplasma genitalium, Cryptosporidium parvum, and Plasmodium falciparum. Analyses conducted in this study revealed that the most active analogue, xanthoquinodin A1, also inhibits Toxoplasma gondii tachyzoites and the liver stage of Plasmodium berghei, with no cross-resistance to the known antimalarial targets PfACS, PfCARL, PfPI4K, or DHODH. In Plasmodium, inhibition occurs prior to multinucleation and induces parasite death following 12 h of compound exposure. This moderately fast activity has impeded resistance line generation, with xanthoquinodin A1 demonstrating an irresistible phenotype in both T. gondii and P. falciparum.

2023-03-10·ACS Infectious Diseases

Fast-Killing Tyrosine Amide ((S)-SW228703) with Blood- and Liver-Stage Antimalarial Activity Associated with the Cyclic Amine Resistance Locus (PfCARL)

Article

作者: Crespo-Fernandez, Benigno ; Gahalawat, Suraksha ; Posner, Bruce A. ; Wittlin, Sergio ; Baum, Jake ; Ready, Joseph M. ; Niederstrasser, Hanspeter ; Mittal, Nimisha ; Winzeler, Elizabeth A. ; Imlay, Leah S. ; Laleu, Benoit ; Xing, Chao ; Lawong, Aloysus K. ; Phillips, Margaret A. ; Kumar, Ashwani ; Churchyard, Alisje ; Gamo, Francisco-Javier

Current malaria treatments are threatened by drug resistance, and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their targets are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for the activity of (S)-SW703, suggesting differences in the mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity for multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.

2021-12-10·ACS Infectious Diseases2区 · 医学

Plasmodium falciparum Acetyl-CoA Synthetase Is Essential for Parasite Intraerythrocytic Development and Chromatin Modification

2区 · 医学

Article

作者: Krüger, Arne ; Wunderlich, Gerhard ; Setubal, João Carlos ; Cubillos, Eliana Fernanda Galindo ; Barbosa, Deibs ; Prata, Isadora Oliveira ; Martins, Joaquim

The malaria parasite Plasmodium falciparum possesses a unique Acetyl-CoA Synthetase (PfACS), which provides acetyl moieties for different metabolic and regulatory cellular pathways. We characterized PfACS and studied its role focusing on epigenetic modifications using the var gene family as reporter genes. For this, mutant lines to modulate plasmodial ACS expression by degron-mediated protein degradation and ribozyme-induced transcript decay were created. Additionally, an inhibitor of the human Acetyl-CoA Synthetase 2 was tested for its effectiveness in interfering with PfACS. The knockdown of PfACS or its inhibition resulted in impaired parasite growth. Decreased levels of PfACS also led to differential histone acetylation patterns, altered variant gene expression, and concomitantly decreased cytoadherence of infected red blood cells containing knocked-down parasites. Further, ChIP analysis revealed the presence of PfACS in many loci in ring stage parasites, underscoring its involvement in the regulation of chromatin. Due to its central function in the plasmodial metabolism and significant differences to human ACS, PfACS is an interesting target for drug development.