Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts

Author:

Rodríguez-Hernández Diego,Vijayan Kamalakannan,Zigweid Rachael,Fenwick Michael K.ORCID,Sankaran BanumathiORCID,Roobsoong WanlapaORCID,Sattabongkot JetsumonORCID,Glennon Elizabeth K. K.,Myler Peter J.ORCID,Sunnerhagen PerORCID,Staker Bart L.,Kaushansky AlexisORCID,Grøtli MortenORCID

Abstract

AbstractDrugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs. Herein, we apply a structure-guided hybridization approach combining chemical moieties of previously reported NMT inhibitors to develop the next generation of PvNMT inhibitors. A high-resolution crystal structure of PvNMT bound to a representative selective hybrid compound reveals a unique binding site architecture that includes a selective conformation of a key tyrosine residue. The hybridized compounds significantly decrease P. falciparum blood-stage parasite load and consistently exhibit dose-dependent inhibition of P. vivax liver stage schizonts and hypnozoites. Our data demonstrate that hybridized NMT inhibitors can be multistage antimalarials, targeting dormant and developing forms of liver and blood stage.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Reference62 articles.

1. Organization, W. H. World malaria report 2021. (2021).

2. Price, R. N. et al. Vivax malaria: neglected and not benign. Am. J. Trop. Med. Hyg. 77, 79–87 (2007).

3. Organization, W. H. World malaria report 2018. (2018).

4. Tse, E. G., Korsik, M. & Todd, M. H. The past, present and future of anti-malarial medicines. Malar. J. 18, 93 (2019).

5. Vijayan, K. et al. Host-targeted Interventions as an exciting opportunity to combat malaria. Chem. Rev. 121, 10452–10468 (2021).

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3