2. Academic Validation
  3. YL1004 is a SARS-CoV-2 papain-like protease inhibitor with immunomodulatory and antiviral activity in mice

YL1004 is a SARS-CoV-2 papain-like protease inhibitor with immunomodulatory and antiviral activity in mice

  • Nat Commun. 2026 Jan 26;17(1):2035. doi: 10.1038/s41467-026-68795-5.
Jinshan Nan # 1 2,  Huiping Shuai # 3,  Jingxin Qiao # 1 2,  Rui Zeng # 1,  Lianzhao Du # 3,  Yan Chen # 1 2,  Chaemin Yoon 3,  Jiaheng Hu 3,  Wenyu Guo 3,  Lei Wang 3,  Chong Huang 1 2,  Lengjing Zhu 1 2,  Yueshan Li 1 2,  Shanshan Zhang 1 2,  Xinyue Deng 1,  Jingxuan Sun 1,  Le Du 1 2,  Ronggang Ma 1 2,  Qiao Huang 1 2,  Jian Lei 4,  Hin Chu 5 6,  Shengyong Yang 7 8
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 3 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China.
  • 4 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. leijian@scu.edu.cn.
  • 5 State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China. hinchu@hku.hk.
  • 6 Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, Hong Kong Special Administrative Region, China. hinchu@hku.hk.
  • 7 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China. yangsy@scu.edu.cn.
  • 8 New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China. yangsy@scu.edu.cn.
  • # Contributed equally.
PMID: 41587976 DOI: 10.1038/s41467-026-68795-5
Abstract

The evolution of SARS-CoV-2, coupled with its immune evasion mechanisms, underscores the urgent need for Antiviral strategies beyond vaccination. The papain-like protease (PLpro) is a dual-functional enzyme essential for viral replication and suppression of host innate immunity. Here, we present the rational design and characterization of YL1004, a tricyclic oral PLpro inhibitor demonstrating robust, cross-variant SARS-CoV-2 Antiviral activity and favorable pharmacokinetic properties. YL1004 potently inhibits the enzymatic function of PLpro, disrupts deubiquitination and deISGylation processes, and restores Antiviral immune signaling cascades. Notably, YL1004 suppresses the replication of SARS-CoV-2 wildtype, Delta and Omicron variants. Additionally, it is also effective against the Mpro E166V recombinant SARS-CoV-2 strain, which confers resistance to nirmatrelvir. In the lethal SARS-CoV-2 Infection model using K18-hACE2 mice, YL1004 confers complete protection to animal survival, significantly reduces viral load in nasal turbinate and lung tissues, and alleviates virus-induced pathological tissue damages. Co-crystal structural analysis revealed a distinctive binding mode, enhancing target engagement through expanded hydrophobic interactive interface and additional hydrogen bonding interactions. Collectively, these findings establish YL1004 as a promising therapeutic candidate, harnessing dual Antiviral and immunomodulatory mechanisms to combat SARS-CoV-2 and emerging variants.

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