Notes on 'Structural Basis of Herpesvirus Helicase-Primase Inhibition by Pritelivir and Amenamevir'

Introduction

• Herpesviruses are double-stranded DNA viruses that cause lifelong infections.
• HSV-1, a common human herpesvirus, requires a helicase-primase (HP) complex for DNA replication.
• HP complex consists of UL5 (helicase), UL52 (primase), and UL8 (auxiliary).
• Pritelivir and amenamevir are inhibitors identified to target this complex but binding mechanisms were unknown.

Structural Basis of HP Complex Inhibition

• Cryo-EM structures reveal HSV-1 HP complex bound to DNA and inhibitors pritelivir or amenamevir.
• The HP complex has a bilobed architecture, crucial for coordinated helicase and primase activity.
• Inhibitors bind in a way that blocks helicase action, providing insights into antiviral drug development.

UL52 Primase Subunit

• UL52 acts as a scaffold, has three domains: N-terminal (NTD), middle (MD), and C-terminal (CTD).
• Contains motifs characteristic of the AEP superfamily.
• MD includes catalytic sites similar to human primase, suggesting binding pockets for ATP and metal ions.

UL5 Helicase Subunit

• Part of the helicase superfamily 1 with seven conserved motifs.
• Uses ATP hydrolysis for DNA translocation (3’ to 5’ direction).
• Significant structural differences from other SF1 helicases, indicating unique features.

UL8 Auxiliary Subunit

• Lacks intrinsic enzymatic activity but essential for viral DNA replication.
• Stimulates activities of UL5 and UL52 in presence of ICP8.
• Shares partial structural similarity with B-family DNA polymerases.

Interaction Sites and Inhibitor Binding

• Inhibitor-bound structures show binding sites and provide insights into inhibition mechanism.
• Pritelivir and amenamevir bind at UL5-UL52 interface, affecting structural dynamics of the complex.

Pritelivir

• Pritelivir interacts with residues at UL5-UL52 interface.
• Causes subtle shifts in surrounding residues upon binding.

Amenamevir

• Amenamevir has a bulkier structure than pritelivir.
• Causes shifts in UL5 Y882 and N342, disrupting inhibitor docking.

Mechanism of Inhibition

• HP inhibitors prevent movement between UL5 domains 1A and 2A, restricting helicase activity.
• Inhibitors do not directly compete with ATP but prevent the necessary conformational changes for helicase function.

Conclusion

• The study provides detailed structural insights into the HSV-1 HP complex and its inhibition by pritelivir and amenamevir.
• Findings can guide the development of improved antiviral therapies.