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

Gao，Qingtian1; Liu，Sixu2; Zhou，Yuzheng3; Fan，Jinbao1; Ke，Shufen1; Zhou，Yuqing2; Fan，Kaiqiang1; Wang，Yuxuan2; Zhou，Yingjun1,4; Xia，Zanxian2; Deng，Xu1,4

2024-07-05

10.1016/j.ejmech.2024.116498

European Journal of Medicinal Chemistry   影响因子和分区

0223-5234

1768-3254

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) 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 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 with high binding affinity. Notably, S5-28 provided significant protection against wild-type SARS-CoV-2 in HeLa-hACE2 cells, with EC 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.

Mpro inhibitors Meisoindigo SARS-CoV-2 Structure-activity relationship

SCI

英语

其他

CHEMISTRY

2-s2.0-85193445021

Scopus

1.Xiangya School of Pharmaceutical Sciences,Central South University,Changsha,Hunan,410013,China
2.School of Life Sciences,Central South University,Changsha,Hunan,410013,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.Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases,Central South University,Changsha,Hunan,410013,China

Gao，Qingtian,Liu，Sixu,Zhou，Yuzheng,et al. Discovery of meisoindigo derivatives as noncovalent and orally available Mpro inhibitors: their therapeutic implications in the treatment of COVID-19[J]. European Journal of Medicinal Chemistry,2024,273.

Gao，Qingtian.,Liu，Sixu.,Zhou，Yuzheng.,Fan，Jinbao.,Ke，Shufen.,...&Deng，Xu.(2024).Discovery of meisoindigo derivatives as noncovalent and orally available Mpro inhibitors: their therapeutic implications in the treatment of COVID-19.European Journal of Medicinal Chemistry,273.

Gao，Qingtian,et al."Discovery of meisoindigo derivatives as noncovalent and orally available Mpro inhibitors: their therapeutic implications in the treatment of COVID-19".European Journal of Medicinal Chemistry 273(2024).