Bioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2

Dongtak Lee; Hyo Gi Jung; Dongsung Park; Junho Bang; Da Yeon Cheong; Jae Won Jang; Yonghwan Kim; Seungmin Lee; Sang Won Lee; Gyudo Lee; Yeon Ho Kim; Ji Hye Hong; Kyo Seon Hwang; Jeong Hoon Lee; Dae Sung Yoon

doi:10.1038/s41467-024-46296-7

Bioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2

Nat Commun. 2024 Mar 7;15(1):2108. doi: 10.1038/s41467-024-46296-7.

Authors

Dongtak Lee^#^{1

2

3}, Hyo Gi Jung^#^{1

4}, Dongsung Park^#^{1

5}, Junho Bang^{1

4}, Da Yeon Cheong^{6

7}, Jae Won Jang^{1

4}, Yonghwan Kim^{1

4}, Seungmin Lee^{1

8}, Sang Won Lee^{1

9}, Gyudo Lee^{6

7}, Yeon Ho Kim^{1

4}, Ji Hye Hong^{1

8}, Kyo Seon Hwang¹⁰, Jeong Hoon Lee¹¹, Dae Sung Yoon^{12

13

14}

Affiliations

¹ School of Biomedical Engineering, Korea University, Seoul, 02841, South Korea.
² Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
³ Harvard Medical School, Boston, MA, 02115, USA.
⁴ Interdisciplinary Program in Precision Public Health, Korea University, Seoul, 02841, South Korea.
⁵ Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, 02447, South Korea.
⁶ Department of Biotechnology and Bioinformatics, Korea University, Sejong, 30019, South Korea.
⁷ Interdisciplinary Graduate Program for Artificial Intelligence Smart Convergence Technology, Korea University, Sejong, 30019, South Korea.
⁸ Department of Electrical Engineering, Kwangwoon University, Seoul, 01897, South Korea.
⁹ Terasaki Institute for Biomedical Innovation, Los Angeles, CA, 90064, USA.
¹⁰ Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, 02447, South Korea. k.hwang@khu.ac.kr.
¹¹ Department of Electrical Engineering, Kwangwoon University, Seoul, 01897, South Korea. jhlee@kw.ac.kr.
¹² School of Biomedical Engineering, Korea University, Seoul, 02841, South Korea. dsyoon@korea.ac.kr.
¹³ Interdisciplinary Program in Precision Public Health, Korea University, Seoul, 02841, South Korea. dsyoon@korea.ac.kr.
¹⁴ Astrion Inc, Seoul, 02841, South Korea. dsyoon@korea.ac.kr.

^# Contributed equally.

Abstract

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has evoked a worldwide pandemic. As the emergence of variants has hampered the neutralization capacity of currently available vaccines, developing effective antiviral therapeutics against SARS-CoV-2 and its variants becomes a significant challenge. The main protease (M^pro) of SARS-CoV-2 has received increased attention as an attractive pharmaceutical target because of its pivotal role in viral replication and proliferation. Here, we generated a de novo M^pro-inhibitor screening platform to evaluate the efficacies of M^pro inhibitors based on M^pro cleavage site-embedded amyloid peptide (MCAP)-coated gold nanoparticles (MCAP-AuNPs). We fabricated MCAPs comprising an amyloid-forming sequence and M^pro-cleavage sequence, mimicking in vivo viral replication process mediated by M^pro. By measuring the proteolytic activity of M^pro and the inhibitory efficacies of various drugs, we confirmed that the MCAP-AuNP-based platform was suitable for rapid screening potential of M^pro inhibitors. These results demonstrated that our MCAP-AuNP-based platform has great potential for discovering M^pro inhibitors and may accelerate the development of therapeutics against COVID-19.

MeSH terms

Antiviral Agents / pharmacology
COVID-19*
Gold / pharmacology
Humans
Metal Nanoparticles*
Molecular Docking Simulation
Peptide Hydrolases
Peptides
Protease Inhibitors / pharmacology
SARS-CoV-2
Viral Nonstructural Proteins

Substances

Gold
Protease Inhibitors
Viral Nonstructural Proteins
Peptides
Peptide Hydrolases
Antiviral Agents

Abstract

MeSH terms

Substances

Grants and funding