iPSC Neuronal Assay Identifies Amaryllidaceae Pharmacophore with Multiple Effects against Herpesvirus Infections

James McNulty; Leonardo D'Aiuto; Yun Zhi; Lora McClain; Carlos Zepeda-Velázquez; Spencer Ler; Hilary A Jenkins; Michael B Yee; Paolo Piazza; Robert H Yolken; Paul R Kinchington; Vishwajit L Nimgaonkar

doi:10.1021/acsmedchemlett.5b00318

iPSC Neuronal Assay Identifies Amaryllidaceae Pharmacophore with Multiple Effects against Herpesvirus Infections

ACS Med Chem Lett. 2015 Nov 19;7(1):46-50. doi: 10.1021/acsmedchemlett.5b00318. eCollection 2016 Jan 14.

Affiliations

¹ Department of Chemistry and Chemical-Biology, McMaster University , 1280 Main Street, West Hamilton, Ontario L8S 4M1, Canada.
² Department of Psychiatry, University of Pittsburgh, School of Medicine , 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213, United States.
³ Department of Psychiatry, University of Pittsburgh, School of Medicine, 3811 O'Hara Street, Pittsburgh, Pennsylvania 15213, United States; Department of Human Genetics, University of Pittsburgh, Graduate School of Public Health, 130 De Soto Street, Pittsburgh, Pennsylvania 15213, United States.
⁴ Department of Ophthalmology, University of Pittsburgh School of Medicine , 203 Lothrop Street, Pittsburgh Pennsylvania 15213, United States.
⁵ Department of Human Genetics, University of Pittsburgh, Graduate School of Public Health , 130 De Soto Street, Pittsburgh, Pennsylvania 15213, United States.
⁶ Department of Pediatrics, Johns Hopkins University School of Medicine , 600 North Wolfe Street, Baltimore, Maryland 21287, United States.

Abstract

The Amaryllidaceae alkaloid trans-dihydrolycoricidine 7 and three analogues 8-10 were produced via asymmetric chemical synthesis. Alkaloid 7 proved superior to acyclovir, the current standard for herpes simplex virus, type 1 (HSV-1) infection. Compound 7 potently inhibited lytic HSV-1 infection, significantly reduced HSV-1 reactivation, and more potently inhibited varicella zoster virus (VZV) lytic infection. A configurationally defined (3R)-secondary alcohol at C3 proved crucial for efficacious inhibition of lytic HSV-1 infection.

Keywords: Amaryllidaceae; HSV-1; Herpesvirus; alkaloid; stem cells; varicella zoster.

Grants and funding

R01 MH042191/MH/NIMH NIH HHS/United States