靶向疟原虫和登革热传播媒介埃及伊蚊和致倦库蚊中氨酰-tRNA 合成酶的药物。

Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue.

机构信息

Molecular Medicine Group, National Institute of Malaria Research, New Delhi, India.

Molecular Medicine, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.

出版信息

Parasit Vectors. 2021 Dec 11;14(1):605. doi: 10.1186/s13071-021-05106-5.

DOI:10.1186/s13071-021-05106-5

PMID:34895309

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8665550/

Abstract

BACKGROUND

Mosquito-borne diseases have a devastating impact on human civilization. A few species of Anopheles mosquitoes are responsible for malaria transmission, and while there has been a reduction in malaria-related deaths worldwide, growing insecticide resistance is a cause for concern. Aedes mosquitoes are known vectors of viral infections, including dengue, yellow fever, chikungunya, and Zika. Aminoacyl-tRNA synthetases (aaRSs) are key players in protein synthesis and are potent anti-infective drug targets. The structure-function activity relationship of aaRSs in mosquitoes (in particular, Anopheles and Aedes spp.) remains unexplored.

METHODS

We employed computational techniques to identify aaRSs from five different mosquito species (Anopheles culicifacies, Anopheles stephensi, Anopheles gambiae, Anopheles minimus, and Aedes aegypti). The VectorBase database ( https://vectorbase.org/vectorbase/app ) and web-based tools were utilized to predict the subcellular localizations (TargetP-2.0, UniProt, DeepLoc-1.0), physicochemical characteristics (ProtParam), and domain arrangements (PfAM, InterPro) of the aaRSs. Structural models for prolyl (PRS)-, and phenylalanyl (FRS)-tRNA synthetases-were generated using the I-TASSER and Phyre protein modeling servers.

RESULTS

Among the vector species, a total of 37 (An. gambiae), 37 (An. culicifacies), 37 (An. stephensi), 37 (An. minimus), and 35 (Ae. aegypti) different aaRSs were characterized within their respective mosquito genomes. Sequence identity amongst the aaRSs from the four Anopheles spp. was > 80% and in Ae. aegypti was > 50%.

CONCLUSIONS

Structural analysis of two important aminoacyl-tRNA synthetases [prolyl (PRS) and phenylanalyl (FRS)] of Anopheles spp. suggests structural and sequence similarity with potential antimalarial inhibitor [halofuginone (HF) and bicyclic azetidine (BRD1369)] binding sites. This suggests the potential for repurposing of these inhibitors against the studied Anopheles spp. and Ae. aegypti.

摘要

背景

蚊媒疾病对人类文明造成了毁灭性的影响。少数几种疟蚊负责传播疟疾，尽管全球因疟疾相关死亡的人数有所减少，但抗杀虫剂的能力不断增强令人担忧。埃及伊蚊是包括登革热、黄热病、基孔肯雅热和寨卡病毒在内的病毒感染的传播媒介。氨酰-tRNA 合成酶（aaRS）是蛋白质合成的关键因子，也是有效的抗感染药物靶点。蚊媒（特别是按蚊和埃及伊蚊）中 aaRS 的结构-功能-活性关系尚未得到探索。

方法

我们使用计算技术从五个不同的蚊子物种（库蚊、致倦库蚊、冈比亚按蚊、微小按蚊和埃及伊蚊）中鉴定出 aaRS。使用 VectorBase 数据库（https://vectorbase.org/vectorbase/app）和基于网络的工具预测 aaRS 的亚细胞定位（TargetP-2.0、UniProt、DeepLoc-1.0）、理化特性（ProtParam）和结构域排列（PfAM、InterPro）。使用 I-TASSER 和 Phyre 蛋白建模服务器生成脯氨酰（PRS）和苯丙氨酰（FRS）tRNA 合成酶的结构模型。