R430: A potent inhibitor of DNA and RNA viruses

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.

Primate simplexviruses differ in tropism for macaque cells

“…McHV1 replicated efficiently in this cell system, in agreement with observations for HSV1 in human brain organoids [60,61]. In sum, we observed a differential capacity of primate simplexviruses to infect rhesus macaque cells.…”

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs

“…22 The platform enables us to compare our expression profile with biosets from studies that are defined as a ranked list of genes corresponding to a specific treatment of a compound. 23 In previous work, 24 we observed a series of transcriptomics changes from HSV-1 acutely infected human neurons. The transcriptomic data were imported into the Correlation Engine as the blueprint to conduct a drug-infection matching at transcriptomics level.…”

“…The expression signature we input into the Correlation Engine are a list of genes with fold changes that reflect expression changes between normal hiPSC-derived neurons and those exposed to HSV-1 and undergoing acute infection (MOI = 0.3, data available at https://www.ncbi.nlm.nih.go-v/geo/query/acc.cgi?acc=GSE111656). 24 This list is referred to as ‘bioset’ in the following contexts. One could consider the bioset the primary entity in subsequent analyses, consisting of a ranked list of elements (genes, probes, proteins, compounds, single-nucleotide variants [SNVs], sequence regions, etc.)…”

Medicinal plants and natural compounds against acyclovir-resistant HSV infections

“…Furthermore, extracts containing catechin and condensed tannins have been reported to inhibit HSV adsorption and replication (De Bruyne et al, 1999;Serkedjieva and Ivancheva, 1999). Peppermint oil, an essential oil extracted from the leaves of Mentha piperita L., mainly consists of methanol (42.8%), menthone (14.6%), isomenthone (5.9%), menthylacetate (4.4%), Wang et al, 2011;Jin et al, 2015;Lei et al, 2019;Li et al, 2019;Wang et al, 2020;Shan et al, 2021 153 Clinical isolate TK mutant Wang et al, 2011;Jin et al, 2015;Lei et al, 2019;Li et al, 2019;Wang et al, 2020;Shan et al, 2021 Blue Cultured in lab TK deletion Jin et al, 2015;Li et al, 2019;Luo et al, 2020;Wang et al, 2020;Shan et al, 2021 A4-3 Cultured in lab TK deletion Hayashi et al, 1997;Hayashi et al, 2012 PAAr Cultured in lab DNA polymerase mutant Honess and Watson, 1977;Jofre et al, 1977;Bourinbaiar and Lee-Huang, 1996;Yoshida et al, 1996;Xu et al, 1999;D'Aiuto et al, 2018…”

“…Transdihydrolycoricidine (R430) is a lycorane-type alkaloid derivative from the Amaryllidaceae family that showed more potent antiviral activity against HSV-1 ACVr strains TK mutant and PAAr compared to ACV. R430 influenced the early stages of the HSV-1 lytic phase principally by reducing the transcription and translation of the viral immediate early (IE) gene ICP4 and DNA polymerase, which may be a consequence of upregulation of STAT3 ( D'Aiuto et al, 2018 ).…”