TY - JOUR
T1 - R430
T2 - A potent inhibitor of DNA and RNA viruses
AU - D’Aiuto, Leonardo
AU - McNulty, James
AU - Hartline, Caroll
AU - Demers, Matthew
AU - Kalkeri, Raj
AU - Wood, Joel
AU - McClain, Lora
AU - Chattopadhyay, Ansuman
AU - Zhi, Yun
AU - Naciri, Jennifer
AU - Smith, Adam
AU - Yolken, Robert
AU - Chowdari, Kodavali
AU - Zepeda-Velazquez, Carlos
AU - Dokuburra, Chanti Babu
AU - Marques, Ernesto
AU - Ptak, Roger
AU - Kinchington, Paul
AU - Watkins, Simon
AU - Prichard, Mark
AU - Bloom, David
AU - Nimgaonkar, Vishwajit
N1 - Funding Information:
We thank the CuraZika Pilot Grant Program. Funded in part by grants from the Stanley Medical Research Institute (07R-1712) and NIH (MH63480, NS096405). We thank the NIAID Division of Microbiology and Infectious Diseases for facilitating the antiviral assays. Work performed in the laboratory of MNP was funded in whole or in part by the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, under contract HHSN272201100016I, Task Order HHSN27200013. PRK acknowledges NIH awards AI22640 and EY08098; and unrestricted grants from Research to Prevent Blindness Inc and Eye & Ear Foundation of Pittsburgh.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-018-33904-y
DO - 10.1038/s41598-018-33904-y
M3 - Article
C2 - 30413769
AN - SCOPUS:85056288811
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 16662
ER -