R430: A potent inhibitor of DNA and RNA viruses

Leonardo D’Aiuto, James McNulty, Caroll Hartline, Matthew Demers, Raj Kalkeri, Joel Wood, Lora McClain, Ansuman Chattopadhyay, Yun Zhi, Jennifer Naciri, Adam Smith, Robert Yolken, Kodavali Chowdari, Carlos Zepeda-Velazquez, Chanti Babu Dokuburra, Ernesto Marques, Roger Ptak, Paul Kinchington, Simon Watkins, Mark PrichardDavid Bloom, Vishwajit Nimgaonkar

Research output: Contribution to journalArticlepeer-review

Abstract

Acyclovir (ACV) is an effective antiviral agent for treating lytic Herpes Simplex virus, type 1 (HSV-1) infections, and it has dramatically reduced the mortality rate of herpes simplex encephalitis. However, HSV-1 resistance to ACV and its derivatives is being increasingly documented, particularly among immunocompromised individuals. The burgeoning drug resistance compels the search for a new generation of more efficacious anti-herpetic drugs. We have previously shown that trans-dihydrolycoricidine (R430), a lycorane-type alkaloid derivative, effectively inhibits HSV-1 infections in cultured cells. We now report that R430 also inhibits ACV-resistant HSV-1 strains, accompanied by global inhibition of viral gene transcription and enrichment of H3K27me3 methylation on viral gene promoters. Furthermore, we demonstrate that R430 prevents HSV-1 reactivation from latency in an ex vivo rodent model. Finally, among a panel of DNA viruses and RNA viruses, R430 inhibited Zika virus with high therapeutic index. Its therapeutic index is comparable to standard antiviral drugs, though it has greater toxicity in non-neuronal cells than in neuronal cells. Synthesis of additional derivatives could enable more efficacious antivirals and the identification of active pharmacophores.

Original languageEnglish (US)
Article number16662
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • General

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