title: A translation inhibitor that suppresses dengue virus in vitro and in vivo.
abstract: We describe a novel translation inhibitor that has anti-dengue virus (DENV) activity in vitro and in vivo. The inhibitor was identified through a high-throughput screening using a DENV infection assay. The compound contains a benzomorphan core structure. Mode-of-action analysis indicated that the compound inhibits protein translation in a viral RNA sequence-independent manner. Analysis of the stereochemistry demonstrated that only one enantiomer of the racemic compound inhibits viral RNA translation. Medicinal chemistry was performed to eliminate a metabolically labile glucuronidation site of the compound to improve its in vivo stability. Pharmacokinetic analysis showed that upon a single subcutaneous dosing of 25 mg/kg of body weight in mice, plasma levels of the compound reached a C(max) (maximum plasma drug concentration) above the protein-binding-adjusted 90% effective concentration (EC(90)) value of 0.96 μM. In agreement with the in vivo pharmacokinetic results, treatment of DENV-infected mice with 25 mg/kg of compound once per day reduced peak viremia by about 40-fold. However, mice treated with 75 mg/kg of compound per day exhibited adverse effects. Collectively, our results demonstrate that the benzomorphan compounds inhibit DENV through suppression of RNA translation. The therapeutic window of the current compounds needs to be improved for further development.
authors: Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos Building, Singapore 138670, Singapore.
authors: Qing-Yin
authors: QY
authors: Wang
authors: Ravinder Reddy
authors: RR
authors: Kondreddi
authors: Xuping
authors: X
authors: Xie
authors: Ranga
authors: R
authors: Rao
authors: Shahul
authors: S
authors: Nilar
authors: Hao Ying
authors: HY
authors: Xu
authors: Min
authors: M
authors: Qing
authors: David
authors: D
authors: Chang
authors: Hongping
authors: H
authors: Dong
authors: Fumiaki
authors: F
authors: Yokokawa
authors: Suresh B
authors: SB
authors: Lakshminarayana
authors: Anne
authors: A
authors: Goh
authors: Wouter
authors: W
authors: Schul
authors: Laura
authors: L
authors: Kramer
authors: Thomas H
authors: TH
authors: Keller
authors: Pei-Yong
authors: PY
authors: Shi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D012367:RNA, Viral / Q000235:genetics; D051381:Rats; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral