Design, synthesis, and biological evaluation of novel AAK1/HDACs dual inhibitors against SARS-CoV-2 entry

Nian-Dong Mao; Yueying Xu; Xia Yao; Yuan Gao; Zi Hui; Hao Che; Chenchen Wang; Jinshan Lu; Jie Yu; Suwen Hu; Hang Zhang; Xiang-Yang Ye

doi:10.1016/j.bioorg.2024.107973

Design, synthesis, and biological evaluation of novel AAK1/HDACs dual inhibitors against SARS-CoV-2 entry

Bioorg Chem. 2024 Nov 19:153:107973. doi: 10.1016/j.bioorg.2024.107973. Online ahead of print.

Authors

Nian-Dong Mao¹, Yueying Xu², Xia Yao², Yuan Gao³, Zi Hui², Hao Che², Chenchen Wang⁴, Jinshan Lu⁵, Jie Yu⁵, Suwen Hu⁶, Hang Zhang⁷, Xiang-Yang Ye⁸

Affiliations

¹ School of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
² School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
³ Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, China.
⁴ School of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
⁵ School of Basic Medical Science, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
⁶ Fujian Provincial Drug Evaluation and Monitoring Center Xiamen Branch, Xiamen, Fujian 361013, China. Electronic address: wenwen2020211@outlook.com.
⁷ School of Basic Medical Science, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: 20090096@hznu.edu.cn.
⁸ School of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines; Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: xyye@hznu.edu.cn.

PMID: 39581172
DOI: 10.1016/j.bioorg.2024.107973

Abstract

AP2-associated protein kinase 1 (AAK1) is a crucial regulator of clathrin-mediated endocytosis, involved in various cellular processes, including viral infection. Histone deacetylases (HDACs) are essential in regulating gene transcription through the process of histone deacetylation and have become promising therapeutic targets for the treatment of cancer and viral infections. In this study, several AAK1/HDACs dual inhibitors based on our previous reported compounds were designed and synthesized, and the antiviral activity of these dual inhibitors were evaluated. Among them, compound 12 showed remarkable dual inhibitory activity against both AAK1 and HDACs, with IC₅₀ values of 15.9 nM for AAK1, 148.7 nM for HDAC1, and 5.2 nM for HDAC6. Notably, this compound exhibited superior efficacy in suppressing SARS-CoV-2 entry into host cells compared to its close analogs 4, 13a, and 13b. Mechanistically, compound 12 attenuated AAK1-induced phosphorylation of adaptor protein-2 μ subunit (AP2M1) threonine 156, disrupting the direct interaction between AP2M1 and ACE2, thus inhibiting the CME-mediated SARS-CoV-2 endocytosis. Additionally, compound 12 increased the acetylation levels of H3K27 and α-tubulin, suggesting its potential as an epigenetic modulator. Overall, our findings propose compound 12 as a promising dual inhibitor against AAK1 and HDACs, highlighting its therapeutic potential in antiviral infections.

Keywords: AAK1; Antivirus; Clathrin-mediated endocytosis; Dual inhibitor; HDACs.