Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19

Mao, Long1; Shaabani, Namir2; Zhang, Xiaoying3; Jin, Can1; Xu, Wanhong3; Argent, Christopher4; Kushnareva, Yulia1; Powers, Colin2; Stegman, Karen2; Liu, Jia1; Xie, Hui2; Xu, Changxu3; Bao, Yimei3; Xu, Lijun3; Zhang, Yuren3; Yang, Haigang3; Qian, Shengdian3; Hu, Yong3; Shao, Jianping3; Zhang, Can3; Li, Tingting3; Li, Yi3; Liu, Na3; Lin, Zhenhao3; Wang, Shanbo3; Wang, Chao3; Shen, Wei3; Lin, Yuanlong5; Shu, Dan5; Zhu, Zhenhong1; Kotoi, Olivia1; Kerwin, Lisa2; Han, Qing6; Chumakova, Ludmila1; Teijaro, John7; Royal, Mike2; Brunswick, Mark2; Allen, Robert2,8; Ji, Henry2; Lu, Hongzhou5; Xu, Xiao1

2024-01-12

10.1016/j.medj.2023.12.004

MED   影响因子和分区

2666-6340

Background: Oral antiviral drugs with improved antiviral potency and safety are needed to address current challenges in clinical practice for treatment of COVID-19, including the risks of rebound, drug-drug interactions, and emerging resistance. Methods: Olgotrelvir (STI-1558) is designed as a next-generation antiviral targeting the SARS-CoV-2 main protease (Mpro), an essential enzyme for SARS-CoV-2 replication, and human cathepsin L (CTSL), a key enzyme for SARS-CoV-2 entry into host cells. Findings: Olgotrelvir is a highly bioavailable oral prodrug that is converted in plasma to its active form, AC1115. The dual mechanism of action of olgotrelvir and AC1115 was confirmed by enzyme activity inhibition assays and co-crystal structures of AC1115 with SARS-CoV-2 Mpro and human CTSL. AC1115 displayed antiviral activity by inhibiting replication of all tested SARS-CoV-2 variants in cell culture systems. Olgotrelvir also inhibited viral entry into cells using SARS-CoV-2 Spikemediated pseudotypes by inhibition of host CTSL. In the K18-hACE2 transgenic mouse model of SARS-CoV-2-mediated disease, olgotrelvir significantly reduced the virus load in the lungs, prevented body weight loss, and reduced cytokine release and lung pathologies. Olgotrelvir demonstrated potent activity against the nirmatrelvir-resistant Mpro E166 mutants. Olgotrelvir showed enhanced oral bioavailability in animal models and in humans with significant plasma exposure without ritonavir. In phase I studies (ClinicalTrials.gov: NCT05364840 and NCT05523739), olgotrelvir demonstrated a favorable safety profile and antiviral activity. Conclusions: Olgotrelvir is an oral inhibitor targeting Mpro and CTSL with high antiviral activity and plasma exposure and is a standalone treatment candidate for COVID-19. Funding: Funded by Sorrento Therapeutics.

ESCI

英语

通讯

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:001161094900001

CELL PRESS

Web of Science

1.ACEA Therapeut Inc, San Diego, CA 92121 USA
2.Sorrento Therapeut Inc, San Diego, CA 92121 USA
3.ACEA Pharmaceut Co Ltd, Hangzhou, Zhejiang, Peoples R China
4.Scientia Clin Res Ltd, Sydney, NSW, Australia
5.SUSTech, Shenzhen Third Peoples Hosp, Shenzhen, Peoples R China
6.Struct Based Design Inc, San Diego, CA 92121 USA
7.Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA
8.Invivyd Inc, Waltham, MA 02451 USA

Mao, Long,Shaabani, Namir,Zhang, Xiaoying,et al. Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19[J]. MED,2024,5(1).

Mao, Long.,Shaabani, Namir.,Zhang, Xiaoying.,Jin, Can.,Xu, Wanhong.,...&Xu, Xiao.(2024).Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19.MED,5(1).

Mao, Long,et al."Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19".MED 5.1(2024).