Discovery of meisoindigo derivatives as noncovalent and orally available Mpro inhibitors: their therapeutic implications in the treatment of COVID-19

Qingtian Gao; Sixu Liu; Yuzheng Zhou; Jinbao Fan; Shufen Ke; Yuqing Zhou; Kaiqiang Fan; Yuxuan Wang; Yingjun Zhou; Zanxian Xia; Xu Deng

doi:10.1016/j.ejmech.2024.116498

Discovery of meisoindigo derivatives as noncovalent and orally available M^pro inhibitors: their therapeutic implications in the treatment of COVID-19

Eur J Med Chem. 2024 May 16:273:116498. doi: 10.1016/j.ejmech.2024.116498. Online ahead of print.

Authors

Qingtian Gao¹, Sixu Liu², Yuzheng Zhou³, Jinbao Fan¹, Shufen Ke¹, Yuqing Zhou², Kaiqiang Fan¹, Yuxuan Wang², Yingjun Zhou⁴, Zanxian Xia⁵, Xu Deng⁶

Affiliations

¹ Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China.
² School of Life Sciences, Central South University, Changsha, 410013, Hunan, China.
³ Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, China.
⁴ Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, Hunan, China.
⁵ School of Life Sciences, Central South University, Changsha, 410013, Hunan, China. Electronic address: xiazanxian@sklmg.edu.cn.
⁶ Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, Hunan, China; Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, 410013, Hunan, China. Electronic address: dengxu3817@csu.edu.cn.

PMID: 38762916
DOI: 10.1016/j.ejmech.2024.116498

Abstract

The progressive emergence of SARS-CoV-2 variants has necessitated the urgent exploration of novel therapeutic strategies to combat the COVID-19 pandemic. The SARS-CoV-2 main protease (M^pro) represents an evolutionarily conserved therapeutic target for drug discovery. This study highlights the discovery of meisoindigo (Mei), derived from the traditional Chinese medicine (TCM) Indigo naturalis, as a novel non-covalent and nonpeptidic M^pro inhibitor. Substantial optimizations and structure-activity relationship (SAR) studies, guided by a structure-based drug design approach, led to the identification of several Mei derivatives, including S5-27 and S5-28, exhibiting low micromolar inhibition against SARS-CoV-2 M^pro with high binding affinity. Notably, S5-28 provided significant protection against wild-type SARS-CoV-2 in HeLa-hACE2 cells, with EC₅₀ up to 2.66 μM. Furthermore, it displayed favorable physiochemical properties and remarkable gastrointestinal and metabolic stability, demonstrating its potential as an orally bioavailable drug for anti-COVID-19 therapy. This research presents a promising avenue for the development of new antiviral agents, offering hope in the ongoing battle against COVID-19.

Keywords: M(pro) inhibitors; Meisoindigo; SARS-CoV-2; Structure-activity relationship.