Limitations of acyclovir and identification of potent HSV antivirals using 3D bioprinted human skin equivalents

S. Tori Ellison, Ian Hayman, Kristy Derr, Paige Derr, Shayne Frebert, Zina Itkin, Min Shen, Anthony Jones, Wendy Olson, Lawrence Corey, Anna Wald, Christine Johnston, Youyi Fong, Marc Ferrer () and Jia Zhu ()
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S. Tori Ellison: National Institutes of Health
Ian Hayman: University of Washington School of Medicine
Kristy Derr: National Institutes of Health
Paige Derr: National Institutes of Health
Shayne Frebert: National Institutes of Health
Zina Itkin: National Institutes of Health
Min Shen: National Institutes of Health
Anthony Jones: University of Washington School of Medicine
Wendy Olson: University of Washington School of Medicine
Lawrence Corey: University of Washington School of Medicine
Anna Wald: University of Washington School of Medicine
Christine Johnston: University of Washington School of Medicine
Youyi Fong: Fred Hutchinson Cancer Center
Marc Ferrer: National Institutes of Health
Jia Zhu: University of Washington School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Herpes simplex virus (HSV) infection poses global public health concerns with lifelong impacts. Acyclovir, the standard therapy, has limited efficacy in preventing subclinical shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. Here we show that acyclovir is significantly less effective in skin-derived keratinocytes than donor-matched fibroblasts. Using 3D bioprinted human skin equivalents (HSEs) in a 96-well plate format, we have screened 738 compounds with broad targets and mechanisms of action, identifying potent antivirals, including 23 known or experimental HSV treatments. Unlike acyclovir, antivirals against HSV helicase/primase or host replication pathways display similar potency across cell types and donor sources in both 2D and 3D models. The reduced potency in keratinocytes may explain acyclovir’s limited clinical efficacy. Our 3D bioprinted HSE assay platform enables the integration of patient-derived cells early in drug development and offers a physiologically relevant approach for HSV drug discovery.

Date: 2025
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DOI: 10.1038/s41467-025-64245-w

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