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

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 (PL^pro) 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 PL^pro inhibitor demonstrating robust, cross-variant SARS-CoV-2 antiviral activity and favorable pharmacokinetic properties. YL1004 potently inhibits the enzymatic function of PL^pro, 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

SUBMITTER: Nan J 

PROVIDER: S-EPMC12946252 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature