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.
James McNulty  1 ,  Leonardo D'Aiuto  2 ,  Yun Zhi  2 ,  Lora McClain  3 ,  Carlos Zepeda-Velázquez  1 ,  Spencer Ler  1 ,  Hilary A Jenkins  1 ,  Michael B Yee  4 ,  Paolo Piazza  5 ,  Robert H Yolken  6 ,  Paul R Kinchington  4 ,  Vishwajit L Nimgaonkar  3
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.
PMID: 26819664 DOI: 10.1021/acsmedchemlett.5b00318
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.