Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein

Wei, Xiafei1; Zhou, Yuzheng1; Shen, Xiaotong1; Fan, Lujie2; Liu, Donglan3; Gao, Xiang1; Zhou, Jian1; Wu, Yezi1; Li, Yunfei1; Feng, Wei1; Zhang, Zheng1

2024-06-01

10.1016/j.apsb.2024.03.009

ACTA PHARMACEUTICA SINICA B   影响因子和分区

2211-3835

2211-3843

The nucleocapsid protein (NP) plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life. Despite its vital role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assembly and host inflammatory response, it remains an unexplored target for drug development. In this study, we identified a small-molecule compound (ciclopirox) that promotes NP degradation using an FDA-approved library and a drug-screening cell model. Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation. Ciclopirox induced abnormal NP aggregation through indirect interaction, leading to the formation of condensates with higher viscosity and lower mobility. These condensates were subsequently degraded via the autophagy-lysosomal pathway, ultimately resulting in a shortened NP half-life and reduced NP expression. Our results suggest that NP is a potential drug target, and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication. 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY -NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

SARS-CoV-2 Nucleocapsid protein Viral replication Ciclopirox Abnormal aggregation Protein degradation Autophagy- lysosome Drug target

SCI

英语

第一 ; 通讯

Shenzhen Science and Technology Program (China)[JCYJ20220530163206015] ; National Key Research and Development Program of China[2021YFA0910900] ; Shenzhen Science and Technology Program (China)[JCYJ20220818103017036] ; National Science Fund for Distinguished Young Scholars (China)[82025022] ; Guangdong Basic and Applied Basic Research Foundation (China)[2023A1515110033] ; Guangdong Science and Technology Plan Project, construction of high-level biosafety laboratories (China)[2021B1212030010]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:001246703300002

INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES

Web of Science

1.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Inst Hepatol, Natl Clin Res Ctr Infect Dis, Shenzhen 518112, Peoples R China
2.Guangzhou Med Univ, Guangzhou Lab, Guangzhou 511495, Peoples R China
3.Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Natl Clin Res Ctr Resp Dis, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou 510120, Peoples R China

Wei, Xiafei,Zhou, Yuzheng,Shen, Xiaotong,et al. Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein[J]. ACTA PHARMACEUTICA SINICA B,2024,14(6).

Wei, Xiafei.,Zhou, Yuzheng.,Shen, Xiaotong.,Fan, Lujie.,Liu, Donglan.,...&Zhang, Zheng.(2024).Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein.ACTA PHARMACEUTICA SINICA B,14(6).

Wei, Xiafei,et al."Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein".ACTA PHARMACEUTICA SINICA B 14.6(2024).