Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound

Sci Rep. 2018 Jan 31;8(1):1925. doi: 10.1038/s41598-018-20362-9.

Abstract

Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Administration, Oral
  • Animals
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics*
  • Antiviral Agents / pharmacology*
  • Benzoates / administration & dosage
  • Benzoates / chemistry
  • Benzoates / pharmacokinetics*
  • Benzoates / pharmacology*
  • Biological Availability
  • Female
  • Humans
  • Mice, Inbred BALB C
  • RNA, Viral / genetics
  • Rift Valley Fever / drug therapy
  • Rift Valley Fever / prevention & control
  • Rift Valley Fever / virology
  • Rift Valley fever virus / drug effects
  • Rift Valley fever virus / physiology*

Substances

  • Antiviral Agents
  • Benzoates
  • RNA, Viral