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Divide et Impera: An In Silico Screening Targeting HCMV ppUL44 Processivity Factor Homodimerization Identifies Small Molecules Inhibiting Viral Replication
Ghassabian, H.; Falchi, F.; Timmoneri, M.; Mercorelli, B.; Loregian, A.; Palù, G.; Alvisi, G. Divide et Impera: An In Silico Screening Targeting HCMV ppUL44 Processivity Factor Homodimerization Identifies Small Molecules Inhibiting Viral Replication. Preprints2020, 2020110560. https://doi.org/10.20944/preprints202011.0560.v1
APA Style
Ghassabian, H., Falchi, F., Timmoneri, M., Mercorelli, B., Loregian, A., Palù, G., & Alvisi, G. (2020). Divide et Impera: An In Silico Screening Targeting HCMV ppUL44 Processivity Factor Homodimerization Identifies Small Molecules Inhibiting Viral Replication. Preprints. https://doi.org/10.20944/preprints202011.0560.v1
Chicago/Turabian Style
Ghassabian, H., Giorgio Palù and Gualtiero Alvisi. 2020 "Divide et Impera: An In Silico Screening Targeting HCMV ppUL44 Processivity Factor Homodimerization Identifies Small Molecules Inhibiting Viral Replication" Preprints. https://doi.org/10.20944/preprints202011.0560.v1
Abstract
Human cytomegalovirus (HCMV) is a leading cause of severe diseases in immunocompromised individuals, including AIDS and transplanted patients, and in congenitally infected newborns. The utility of available drugs is limited by poor bioavailability, toxicity, and emergence of resistant strains. Therefore, it is crucial to identify new targets of therapeutic intervention. Among the latter, viral protein-protein interactions are becoming increasingly attractive. Since dimerization of HCMV DNA polymerase processivity factor ppUL44 plays an essential role in the viral life cycle being required for oriLyt-dependent DNA replication, we performed an in silico screening and selected 18 small molecules (SMs) potentially interfering with ppUL44 homodimerization. Antiviral assays using recombinant HCMV TB40-UL83-YFP in the presence of the selected SMs led to the identification of four active compounds. The most active one, B3, also efficiently inhibited AD169 in plaque reduction assays and impaired replication of an AD169-GFP reporter virus and its ganciclovir-resistant counterpart to a similar extent. As assessed by Western blotting experiments, treatment of infected cells with B3 specifically reduced viral gene expression starting from 48 h post infection, consistent with activity on viral DNA synthesis. Therefore, inhibition of ppUL44 dimerization could represent a new class of HCMV inhibitors, complementary to those targeting the DNA polymerase catalytic subunit or the viral terminase complex.
Keywords
HCMV; protein-protein interactions; small molecules; ppUL44; PAP; pUL54; antivirals; screening
Subject
Biology and Life Sciences, Anatomy and Physiology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.