R430: A potent inhibitor of DNA and RNA viruses

Leonardo D’Aiuto,Matthew Demers,Jennifer Naciri,David C Bloom ,Audrey Smith ,James Mcnulty,Kodavali V Chowdari ,Ernesto T A Marques ,Robert H Yolken ,Yun Zhi,Mark N Prichard ,Simon C Watkins ,Carlos Zepeda-Velázquez ,Joel Wood,Caroll B Hartline ,Lora Mcclain,Ansuman Chattopadhyay,Roger G Ptak ,Paul R Kinchington ,Chanti Babu Dokuburra,Raj Kalkeri,Vishwajit L Nimgaonkar

doi:10.1038/s41598-018-33904-y

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.

Highlights

Human herpes viruses (HHV) infect more than 3.7 billion people world-wide[1,2], causing substantial morbidity[3,4]
Following our earlier studies indicating an inhibitory effect of R430 on productive HSV-1 infection in monkey Vero cells and hiPSC-neurons[18], we show that R430 effectively prevents HSV-1 reactivation in a murine model of HSV-1 latency
The absence of reactivation in mouse trigeminal ganglia (TG) explants is consistent with our earlier studies in a hiPSC-N model of latent HSV-1 infection[18]

Summary

Introduction

Human herpes viruses (HHV) infect more than 3.7 billion people world-wide[1,2], causing substantial morbidity[3,4]. Gabrielsen et al reported on a series of 23 Amaryllidaceae isoquinoline alkaloids and synthetic analogues that possessed inhibitory effects against several viruses, albeit with relatively low margins of safety, against selected flaviruses (Japanese encephalitis, yellow fever, and dengue viruses) as well as bunyaviruses (Punta Toro, and Rift Valley fever viruses)[17] Pancratistatin, another Amaryllidaceae derivative with antineoplastic properties, and its 7-deoxy analogue increased survival in a Japanese-encephalitis-virus-infected mouse model[17]. R430 (3-epi-trans-dihydrolycoricidine) inhibited productive infection with the HSV-1 KOS strain effectively in both monkey epithelial (Vero) cells and in neuronal cells derived from human induced pluripotent stem cells (hiPSC-neurons), with an estimated therapeutic index (TI) over 50018. We investigated the range of antiviral effects of R430 by estimating its potency and toxicity in cellular infection models of Zika virus (ZIKV), Herpes Simplex virus, type 2 (HSV-2), human cytomegalovirus (hCMV), murine CMV (mCMV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV)

Methods

Results

Conclusion