2. Academic Validation
  3. Mechanisms of HSV-1 helicase-primase inhibition and replication fork complex assembly

Mechanisms of HSV-1 helicase-primase inhibition and replication fork complex assembly

  • Cell. 2025 Dec 29:S0092-8674(25)01376-5. doi: 10.1016/j.cell.2025.11.041.
Zishuo Yu 1,  Pradeep Sathyanarayana 2,  Cong Liu 3,  Joel M J Tan 4,  Pan Yang 1,  Biswajit Das 1,  Side Hu 1,  Xiaoyi Fan 1,  Chenggong Ji 1,  Sandra K Weller 5,  Mrinal Shekhar 3,  Donald M Coen 2,  Philip J Kranzusch 4,  Joseph J Loparo 6,  Jonathan Abraham 7
Affiliations

Affiliations

  • 1 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 3 Center for the Development of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 4 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Molecular Biology and Biophysics, University of Connecticut School of Medicine, Farmington, CT, USA.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
  • 7 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA; Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA; Center for Integrated Solutions for Infectious Diseases, Broad Institute of Harvard and MIT, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA. Electronic address: [email protected].
PMID: 41468884 DOI: 10.1016/j.cell.2025.11.041
Abstract

Herpesviruses are widespread double-stranded DNA viruses that establish lifelong latency and cause various diseases. Although DNA-polymerase-targeting antivirals are effective, increasing drug resistance underscores the need for alternatives. Helicase-primase inhibitors (HPIs) are promising antivirals, but their mechanisms of action are poorly defined. Furthermore, how the helicase-primase (H/P) complex and DNA Polymerase coordinate genome replication is not well understood for herpesviruses. Here, we report cryo-electron microscopy (cryo-EM) structures of the herpes simplex virus 1 H/P complex bound to HPIs, showing that these lock the H/P complex in an inactive state. Single-molecule assays reveal that HPIs cause H/P complexes to pause in unwinding activity on DNA. The structure of an HPI-bound replication fork complex, comprising the H/P complex (UL5, UL52, and UL8) and the polymerase holoenzyme (UL30 and UL42), reveals a previously uncharacterized interface bridging these complexes. These findings provide a structural framework for understanding herpesvirus replisome assembly and advancing inhibitor development.

Keywords

DNA replication; antiviral; helicase; herpesvirus; polymerase; primase.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-14809
    99.92%, HSV Inhibitor
    HSV