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
  • 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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