Identification and characterization of bisbenzimide compounds that inhibit human cytomegalovirus replication

Falci Finardi, N., Kim, H., Hernandez, L. Z., Russell, M. R. G., Ho, C. M.-K., Sreenu, V. B. , Wenham, H. A., Merritt, A. and Strang, B. L. (2021) Identification and characterization of bisbenzimide compounds that inhibit human cytomegalovirus replication. Journal of General Virology, 102(12), 001702. (doi: 10.1099/jgv.0.001702) (PMID:34882533)

Abstract

The shortcomings of current anti-human cytomegalovirus (HCMV) drugs has stimulated a search for anti-HCMV compounds with novel targets. We screened collections of bioactive compounds and identified a range of compounds with the potential to inhibit HCMV replication. Of these compounds, we selected bisbenzimide compound RO-90-7501 for further study. We generated analogues of RO-90-7501 and found that one compound, MRT00210423, had increased anti-HCMV activity compared to RO-90-7501. Using a combination of compound analogues, microscopy and biochemical assays we found RO-90-7501 and MRT00210423 interacted with DNA. In single molecule microscopy experiments we found RO-90-7501, but not MRT00210423, was able to compact DNA, suggesting that compaction of DNA was non-obligatory for anti-HCMV effects. Using bioinformatics analysis, we found that there were many putative bisbenzimide binding sites in the HCMV DNA genome. However, using western blotting, quantitative PCR and electron microscopy, we found that at a concentration able to inhibit HCMV replication our compounds had little or no effect on production of certain HCMV proteins or DNA synthesis, but did have a notable inhibitory effect on HCMV capsid production. We reasoned that these effects may have involved binding of our compounds to the HCMV genome and/or host cell chromatin. Therefore, our data expand our understanding of compounds with anti-HCMV activity and suggest targeting of DNA with bisbenzimide compounds may be a useful anti-HCMV strategy.

• Item Type: Articles
• Additional Information: This work was supported by New Investigator funds from St George’s, University of London, St George’s Impact & Innovation Awards (2014 and 2018), a PARK/WestFocus Award, MRC Industrial CASE studentship MR/M016226/1 (all to B.L.S.), plus the University of Texas Rio Grande Valley Start-up Grant and the University of Texas System’s Rising STARs Award (both to H.J.K.). We are grateful to Don Coen (Harvard Medical School) for his support of B.L.S. during the screening experiments featured here via grants awarded to D.C. from the National Institutes of Health (R01 AI019838 and R01 AI026077).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Vattipally, Dr Sreenu

Creator Roles

Sreenu, V. B.: ["credit_typename_" not defined], ["credit_typename_" not defined]

• Authors: Falci Finardi, N., Kim, H., Hernandez, L. Z., Russell, M. R. G., Ho, C. M.-K., Sreenu, V. B., Wenham, H. A., Merritt, A., and Strang, B. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Journal of General Virology
• Publisher: Microbiology Society
• ISSN: 0022-1317
• ISSN (Online): 1465-2099
• Published Online: 09 December 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Journal of General Virology 102(12): 001702
• Publisher Policy: Reproduced under a Creative Commons License