Substrate and inhibitor specificity of Plasmodium nucleoside transporters ENT1 orthologues

Xinyi Chen; Chengyu Tian; Yingying He; Yaozong Li; Yanxia Zhou; Xiang Wang; Mi Zhou; Jingwen Lin; Zhong Lian; Dong Deng

doi:10.1016/j.jbc.2024.108115

Substrate and inhibitor specificity of Plasmodium nucleoside transporters ENT1 orthologues

J Biol Chem. 2024 Dec 24:108115. doi: 10.1016/j.jbc.2024.108115. Online ahead of print.

Authors

Xinyi Chen¹, Chengyu Tian², Yingying He¹, Yaozong Li³, Yanxia Zhou⁴, Xiang Wang¹, Mi Zhou¹, Jingwen Lin⁵, Zhong Lian⁶, Dong Deng⁷

Affiliations

¹ Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu 610041, China.
² West China Biomedical Big Data Center, West China Hospital, Sichuan University.
³ Department of Chemistry, Umeå University, SE-901 87 Umea, Sweden; Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.
⁴ West China School of Basic Medical Sciences & Forensic Medicine,Sichuan University, Chengdu 610041, China.
⁵ Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
⁶ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: lianzhong@scu.edu.cn.
⁷ Department of Obstetrics, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu 610041, China; NHC key Laboratory of Chronobiology, Sichuan University, Chengdu 610041, China. Electronic address: dengd@scu.edu.cn.

PMID: 39725030
DOI: 10.1016/j.jbc.2024.108115

Abstract

Malaria caused by Plasmodium infection poses a serious hazard to human health. P. falciparum equilibrative nucleoside transporter 1 (PfENT1), which mediates nucleoside uptake, is essential for the growth and proliferation of Plasmodium parasites, suggesting that PfENT1 is a potential antimalarial target. The promising compound GSK4 effectively inhibits the transport activity of PfENT1, thereby restraining the growth of Plasmodium parasites. However, it still needs to be clarified whether Plasmodium ENT1 orthologues have different selectivities for nucleosides and inhibitors. Here, we systematically compared the nucleoside selectivity of Plasmodium ENT1 orthologues from P. falciparum (PfENT1), P. berghei (PbENT1), and P. vivax (PvENT1), revealing that Plasmodium ENT1 orthologues present a distinct nucleoside recognition pattern. In addition, GSK4 robustly binds to PfENT1 and PvENT1 from two human-hosted Plasmodium parasites but has a weakened binding affinity for PbENT1 from mouse-hosted Plasmodium parasites. We further structurally optimized the inhibitor and generated three GSK4 analogs. One of the GSK4 analogs presented a slightly increased binding affinity for PfENT1. This optimization represents a promising advancement for antimalarial drug development, providing a novel foundation for future endeavors in antimalarial drug design.