Reuters Health Information (2003-07-10): Aromatic cations inhibit bovine virus, proxy for hepatitis C
Aromatic cations inhibit bovine virus, proxy for hepatitis C
Last Updated: 2003-07-10 16:48:04 -0400 (Reuters Health)
NEW YORK (Reuters Health) - Two aromatic cationic compounds from Immtech International effectively inhibit the bovine viral diarrhea virus (BVDV) in vitro without exhibiting cytotoxicity, according to a report published in the July issue of Antimicrobial Agents and Chemotherapy.
The finding may represent a new opportunity to develop an effective hepatitis C treatment, researchers note. Because the hepatitis C virus does not grow in a cell culture system, BVDV is commonly used as an in vitro model for hepatitis C.
Aromatic dicationic molecules, including those advanced by Immtech, previously have demonstrated an ability to inhibit several single-stranded RNA viruses. In the current study, Dr. M. Daniel Givens, of Auburn University in Alabama, and colleagues sought to develop a method to screen aromatic cationic compounds for in vitro cytotoxicity and activity against BVDV.
From an original group of 93 compounds, the researchers selected five to screen further against a non-cytopathic strain of BVDV. The researchers initially evaluated either 25 micromolar or 5 micromolar concentrations of the five compounds against BVDV in medium and cell lysates after 72 hours of cell culture.
The concentrations of the compounds were further adjusted during the screening to find a suitable range for the inhibitory (90% and 50%) and cytotoxic (50% and 10%) concentration endpoints.
The screening method developed by the researchers identified compounds that inhibited BVDV at a 29 nanomolar concentration, while at the same time exhibiting no cytotoxicity at a 25 micromolar concentration. Dr. Givens said one compound was tested safely at a 54 micromolar concentration without threatening the viability of cells.
"Between 54 micromolars to 29 nanomolars, you have a significant range to discover a compound that may work safely against BVDV or hepatitis C," Dr. Givens, a veterinarian by training, told Reuters Health.
Immtech, based in Vernon Hills, Illinois, said it planned to evaluate specific cationic compounds for anti-hepatitis C activity based on data from this National Institutes of Health-sponsored study.
Unlike many hepatitis C drug discovery efforts, which rely on an electrical pulse to insert the virus into the cell, Dr. Givens said they observed that the cationic compounds naturally bound to the cell membrane of BVDV. The cationic compounds also bound to ribosomes within the cell.
"Through this assay, the compound is not bypassing the virus' entry in to the cell," Dr. Givens said. "The agent is following the natural course of infection."
The investigators note that the cationic compounds require further investigation to determine their mechanisms of action, in vivo activity, and specific activity against hepatitis C virus.