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通过一系列 ATP 类似物靶向脯氨酰-tRNA 合成酶，加速抗弓形虫病药物的发现。

Targeting prolyl-tRNA synthetase via a series of ATP-mimetics to accelerate drug discovery against toxoplasmosis.

机构信息

Molecular Medicine-Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi, India.

Institute for Advanced Biosciences (IAB), Team Host-Pathogen Interactions and Immunity to Infection, INSERM U1209, CNRS UMR5309, Université Grenoble Alpes, Grenoble, France.

出版信息

PLoS Pathog. 2023 Feb 28;19(2):e1011124. doi: 10.1371/journal.ppat.1011124. eCollection 2023 Feb.

DOI:10.1371/journal.ppat.1011124
PMID:36854028
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9974123/
Abstract

The prolyl-tRNA synthetase (PRS) is a validated drug target for febrifugine and its synthetic analog halofuginone (HFG) against multiple apicomplexan parasites including Plasmodium falciparum and Toxoplasma gondii. Here, a novel ATP-mimetic centered on 1-(pyridin-4-yl) pyrrolidin-2-one (PPL) scaffold has been validated to bind to Toxoplasma gondii PRS and kill toxoplasma parasites. PPL series exhibited potent inhibition at the cellular (T. gondii parasites) and enzymatic (TgPRS) levels compared to the human counterparts. Cell-based chemical mutagenesis was employed to determine the mechanism of action via a forward genetic screen. Tg-resistant parasites were analyzed with wild-type strain by RNA-seq to identify mutations in the coding sequence conferring drug resistance by computational analysis of variants. DNA sequencing established two mutations, T477A and T592S, proximal to terminals of the PPL scaffold and not directly in the ATP, tRNA, or L-pro sites, as supported by the structural data from high-resolution crystal structures of drug-bound enzyme complexes. These data provide an avenue for structure-based activity enhancement of this chemical series as anti-infectives.

摘要

脯氨酰-tRNA 合成酶 (PRS) 是法匹拉韦及其合成类似物卤夫酮 (HFG) 针对多种顶复门寄生虫（包括恶性疟原虫和刚地弓形虫）的有效药物靶点。在这里，一种基于 1-(吡啶-4-基)吡咯烷-2-酮 (PPL) 支架的新型 ATP 模拟物已被验证可与刚地弓形虫 PRS 结合并杀死弓形体寄生虫。与相应的人 PRS 相比，PPL 系列在细胞（刚地弓形虫寄生虫）和酶（TgPRS）水平上表现出强大的抑制作用。通过正向遗传筛选，采用基于细胞的化学诱变来确定作用机制。通过计算分析变体，对野生型菌株进行 RNA-seq 分析以鉴定赋予耐药性的编码序列中的突变，从而对 Tg 耐药寄生虫进行分析。通过对药物结合酶复合物的高分辨率晶体结构数据的支持，DNA 测序确定了两个突变，T477A 和 T592S，位于 PPL 支架的末端附近，而不是直接在 ATP、tRNA 或 L-pro 位点。这些数据为该化学系列作为抗感染药物的基于结构的活性增强提供了途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/75641d084ce8/ppat.1011124.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/0ef48e46cca9/ppat.1011124.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/dc43202449f6/ppat.1011124.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/7b6dbd9d0dba/ppat.1011124.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/131733329d79/ppat.1011124.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/2688915fdf83/ppat.1011124.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/9c8db0ae5777/ppat.1011124.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/9de5076c3092/ppat.1011124.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/75641d084ce8/ppat.1011124.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/0ef48e46cca9/ppat.1011124.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/dc43202449f6/ppat.1011124.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/7b6dbd9d0dba/ppat.1011124.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/131733329d79/ppat.1011124.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/2688915fdf83/ppat.1011124.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/9c8db0ae5777/ppat.1011124.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/9de5076c3092/ppat.1011124.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ce0/9974123/75641d084ce8/ppat.1011124.g008.jpg

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