Most drugs that act as antiviral agents directly inhibit the functioning of an essential viral component. Protease inhibitors that directly act on the HIV protease, for example, are very effective anti-AIDS drugs.
Research in the Biology Department at the U. S. Department of Energy's Brookhaven National Laboratory has opened up the possibility of a class of antiviral agents that act indirectly, by inducing the infected cell to synthesize a compound that inhibits the function of an essential viral component. In a paper published in the December issue of the Federation of American Societies for Experimental Biology (FASEB) Journal, our laboratory showed that nitric oxide (NO) inhibited the adenovirus protease, and that adenovirus treated with NO showed a dramatic decrease in infectivity.
Human adenovirus is ubiquitous. It causes viral pink eye and epidemics of colds among army recruits. It can also cause blindness and, in the third world, many children are killed by a diarrhea caused by adenovirus. It participates in opportunistic infections, killing many AIDS patients. There are more than 37 human serotypes of adenovirus, so the prospect of a universal vaccine is unlikely. What is needed is an antiviral agent.
An essential component of adenovirus, as in HIV, is its protease. Normally, this enzyme, which is in the virus particle, becomes activated and "cleaves," or degrades, certain viral proteins to complete the maturation of newly synthesized virus particles. Only once this occurs can the newly synthesized virus particles infect adjacent cells to propagate the viral infection. If the enzyme is inhibited from cleaving certain viral proteins, the virus particle is not infectious and the infection is aborted.
NO is synthesized in many different cells. It is involved in several physiological processes including blood pressure regulation and the transmission of nerve impulses. Enhanced production of NO has been implicated at least partly in hypotension, inflammation-associated tissue damage, rheumatoid arthritis and insulin-dependent diabetes mellitus. Diminished NO production has been implicated in pulmonary hypertension, arteriosclerosis, and reperfusion injury.
We hypothesized that NO would inhibit the adenovirus protease because NO modulates the biological activity of many proteins by reacting with the sulfur atom on the amino acid cysteine. We had previously shown that the crucial amino acid residue in the adenovirus protease is a cysteine residue; modification of it by NO should inactivate the enzyme. We not only showed that NO inhibits the adenovirus protease but went on to biochemically characterize the inhibition. In this collaboration, with Charles Lowenstein's laboratory at the Johns Hopkins University, we showed that adenovirus treated with NO is much less infectious.
All of this raises the possibility that if cells infected by adenovirus can be induced to synthesize NO, then the virus in those cells may be inactivated. For example, an NO inducer may be "sprinkled" onto the eyes of children with viral pink eye. Similarly, the lungs of army recruits infected with adenovirus could be sprayed with an NO inducer to help stop the spread of colds.
Author: Walter Mangel, Ph. D.
Brookhaven National Laboratory firstname.lastname@example.org
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