Hlyc41 disrupts SARS-CoV-2 NSP12 hijacking of Hsc70, promoting degradation and suppressing viral replication

The SARS-CoV-2 pandemic highlighted an urgent need for effective antiviral therapeutics. A key target is nonstructural protein 12 (NSP12), the RNA-dependent RNA polymerase (RdRp), which forms the catalytic core of the viral replication-transcription complex and is essential for viral RNA synthesis. While NSP12's role is critical, the precise mechanisms governing its intracellular stability, which are vital for efficient viral replication, have remained poorly understood. Understanding these regulatory pathways could reveal novel vulnerabilities for antiviral intervention.

Researchers investigated the stability mechanisms of SARS-CoV-2 nonstructural protein 12 (NSP12), the viral RdRp. They identified a previously unrecognized viral strategy where NSP12 hijacks the host chaperone Hsc70 to modulate its own stability. Through mechanistic studies, they elucidated Hsc70's dual role: mediating NSP12 degradation via chaperone-mediated autophagy (CMA) while also promoting its accumulation. They then identified Hlyc41 as a potential antiviral agent by screening for compounds that disrupt this specific NSP12-Hsc70 interaction.

The study revealed that host chaperone Hsc70 plays a dual role in regulating NSP12 levels, both mediating its degradation through chaperone-mediated autophagy (CMA) and promoting its accumulation. The dynamic balance between these opposing functions determines NSP12 fate. Crucially, NSP12 can evade CMA-mediated degradation by binding to Hsc70 with a higher affinity. This strong binding disrupts the normal Hsc70-LAMP2a interaction, shifting Hsc70's primary role towards facilitating NSP12 accumulation, which in turn enhances viral replication. This mechanism represents a novel host hijacking strategy. > Hlyc41 was identified as a potential antiviral agent that effectively disrupts this hijacking mechanism by competing with NSP12 for binding to the F428 residue of Hsc70. This competition promotes NSP12 degradation and consequently suppresses viral replication.