A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication PMID: 33510133

ADC Targets in Oncology

2026-04-10

A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

Nat Commun. 2021 Jan 28;12(1):668. doi: 10.1038/s41467-021-20900-6.

Shin-Ichiro Hattori ¹ , Nobuyo Higashi-Kuwata ¹ , Hironori Hayashi ² ³ , Srinivasa Rao Allu ⁴ , Jakka Raghavaiah ⁴ , Haydar Bulut ⁵ , Debananda Das ⁵ , Brandon J Anson ⁶ , Emma K Lendy ⁶ , Yuki Takamatsu ¹ , Nobutoki Takamune ⁷ , Naoki Kishimoto ⁸ , Kazutaka Murayama ⁹ , Kazuya Hasegawa ¹⁰ , Mi Li ¹¹ ¹² , David A Davis ¹³ , Eiichi N Kodama ³ ¹⁴ , Robert Yarchoan ¹³ , Alexander Wlodawer ¹¹ , Shogo Misumi ⁸ , Andrew D Mesecar ⁶ , Arun K Ghosh ⁴ , Hiroaki Mitsuya ¹⁵ ¹⁶ ¹⁷

Affiliations

1. Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
2. Department of Intelligent Network for Infection Control, Tohoku University Hospital, Miyagi, Japan.
3. Department of infectious Diseases, International Research Institute of Disaster Science, Tohoku University, Miyagi, Japan.
4. Department of Chemistry and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
5. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
6. Department of Biochemistry and Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
7. Kumamoto Innovative Development Organization, Kumamoto University, Kumamoto, Japan.
8. Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
9. Graduate School of Biomedical Engineering, Tohoku University, Miyagi, Japan.
10. Protein Crystal Analysis Division, Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
11. Protein Structure Section, Center for Structural Biology, National Cancer Institute, Frederick, MD, USA.
12. Basic Science Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
13. Viral Oncology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
14. Department of Infectious Diseases, Graduate School of Medicine and Tohoku Medical Megabank Organization, Tohoku University, Miyagi, Japan.
15. Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan. [email protected].
16. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. [email protected].
17. Department of Clinical Sciences, Kumamoto University Hospital, Kumamoto, Japan. [email protected].

Abstract

Except remdesivir, no specific antivirals for SARS-CoV-2 Infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (M^pro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC₅₀ values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 Infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with M^pro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead M^pro inhibitor for the development of therapeutics for SARS-CoV-2 Infection.