DNA primases synthesize short primers required for genome replication, yet the mechanism of initial dinucleotide formation remains poorly understood. Here, we investigate the primase encoded by the pRN1 plasmid from the thermoacidophile archaeon Sulfolobus islandicus, a minimal model for primer synthesis. Using nucleotide analogues to slow the reaction, we capture transient intermediates of dinucleotide formation. Structural NMR and modeling reveal that the ancillary domain simultaneously binds the DNA template and two initiating nucleotides. Unexpectedly, only the second nucleotide base-pairs with the template, whereas the first remains unpaired, inducing template-base flipping and linker interaction. This interaction promotes a closed conformation in which the second nucleotide moves from the initiation to the elongation site and the first forms a base pair in the initiation site, positioning both nucleotides for catalysis. These findings reveal a mechanism for template recognition,

Assembly Biosciences will take a 40% share of US costs and profits for the GS-1179 helicase-primase inhibitor as a Phase 2 trial approaches.

During replisome assembly of monkeypox virus, the hexameric helicase–primase E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 th...

Immunocompromised patients are at risk for severe, prolonged herpes simplex virus (HSV) recurrences. Refractory disease and intolerance to standard therapy drive an unmet medical need. Pritelivir, a novel HSV helicase-primase inhibitor, has shown favorable tolerability and efficacy in immunocompetent adults.MethodsPRIOH-1, a multicenter, randomized, open-label Phase 2 trial, compared oral pritelivir (400-mg loading dose followed by 100 mg daily) with intravenous foscarnet (40 mg/kg q8h or 60 mg/kg q12h) for up to 28 days in immunocompromised adults with acyclovir-refractory HSV (Part A). Participants with refractoriness/intolerance to foscarnet received pritelivir (Part B). The primary end point was time to lesion healing; secondary end points included healing rate, HSV DNA detection, and resistance.ResultsTwenty-two participants enrolled in Part A, 8 in Part B. In Part A, median time to healing was 26.0 days (95% CI, 13.0–31.0) with pritelivir, vs not estimable (95% CI, 20.0–NE) with foscarnet (HR, 2.7; 95% CI, 0.33–21.8; P = .34). Investigator-assessed healing rates were 93% with pritelivir and 57% with foscarnet, a 36.2% difference (95% CI, −10.1 to 74.1; P = .077). Postbaseline HSV DNA detection rates were 34.8% and 50.0%, respectively (P = .42). Treatment-emergent adverse events occurred in 60% of pritelivir- and 100% of foscarnet-treated participants; serious treatment-emergent adverse events were less frequent with pritelivir. In Part B, the median time to healing was 19.0 days, with a 63% healing rate.ConclusionsPritelivir demonstrated encouraging efficacy and favorable safety in immunocompromised adults with limited treatment options, supporting Phase 3 evaluation for the treatment of refractory HSV infection in this population.

During replisome assembly of monkeypox virus, the hexameric helicase–primase E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 th...

The way two mpox virus proteins change shape as they bind together acts like a switch that starts the process of viral replication, a study led by researchers at the Blavatnik Institute at Harvard Medical School reveals.

Assembly Biosciences (ASMB) has exercised its option to share 40% of U.S. development costs and profits for its herpes simplex virus (HSV) helicase-primase inhibitor program for recurrent genital herpes under its collaboration with Gilead Sciences.Gilead retains sole responsibility for clinical development and commercialization of the HSV HPI program, which includes GS-1179 and GS-5366. Assembly Bio is eligible for up to $280 million in regulatory and commercial milestones plus tiered royalties on net sales outside the U.S. ranging from high single-digits to low teens. If the U.S. profit share is ended under either party’s opt-out or conversion rights, economics could shift to up to $330 million in milestones with similar royalty tiers.GS-1179 is expected to enter a Phase 2 trial in recurrent genital herpes by the end of 2026. Including a $75 million continuation payment due from Gilead in Q4 2026, Assembly Bio projects its cash runway into 2029.

During replisome assembly of monkeypox virus, the hexameric helicase–primase E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 thumb domain and A22 subunit, activating the helicase–primase.

During replisome assembly of monkeypox virus, the hexameric helicase–primase E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 th...

Nature, Published online: 02 September 2026; doi:10.1038/s41586-026-10937-2During replisome assembly of monkeypox #virus, the hexameric helicase–primase E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 thumb domain and A22 subunit, activating the helicase–primase.

During replisome assembly of monkeypox virus, the hexameric helicase–primase E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 th...

Nature, Published online: 02 September 2026; doi:10.1038/s41586-026-10937-2During replisome assembly of monkeypox #virus, the hexameric helicase–primase E5 undergoes large-scale conformational changes that allow two of its primase domains to interact with the polymerase F8 thumb domain and A22 subunit, activating the helicase–primase.

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Gene disruption analysis revealed that an E. coli PPRT protein, which has an N-terminal Primase-Polymerase (PrimPol) domain fused to a group II intron-like reverse transcriptase (RT) domain followed b...