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

Discovery of meisoindigo derivatives as noncovalent and orally available Mpro 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.
Qingtian Gao 1,  Sixu Liu 2,  Yuzheng Zhou 3,  Jinbao Fan 1,  Shufen Ke 1,  Yuqing Zhou 2,  Kaiqiang Fan 1,  Yuxuan Wang 2,  Yingjun Zhou 4,  Zanxian Xia 5,  Xu Deng 6
Affiliations

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: [email protected].
  • 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: [email protected].
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 (Mpro) 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 Mpro 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 Mpro 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.

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