First DNA/enzyme model serves as antiviral drug target
enzyme, a crucial step for a virus to cause infection, have been
produced, which shows how binding to DNA may stimulate the enzyme,
aiding to the design of new antiviral drugs to block this
interaction.
During infection, adenovirus' make an enzyme called a protease, which cleaves or degrades viral "scaffolding" proteins to complete the maturation of newly synthesized virus particles.
The scientists believe that inside the virus particle the protease uses the DNA as a guide wire, sliding along the genetic material to remove the internal supporting proteins, all located near the DNA
Dr Walter Mangel, a co-author on the paper, told DrugResearcher.com: "Now that a map of the DNA binding sites has been obtained, drugs will be found that bind to these sites. If the binding of drugs to the enzyme prevents DNA from binding to the enzyme, then, DNA cannot activate the enzyme and the viral infection will be terminated."
The team used a technique called synchrotron footprinting to show where DNA binds on the adenovirus protease.
Synchrotron footprinting is a technique that allows structural information on the contacting surfaces of biological molecules to be precisely mapped. In this study the footprinting approach provided information on the DNA binding region of the adenovirus protease that has not been solved by other techniques and can be used in drug design.
"We determined the crystal structure of this enzyme, so we now know the structures of the DNA binding sites. Since the DNA binding site is quite long, there are numerous locations along it that could be used as targets for drugs to block the interaction and act as antiviral agents," Mangel said.
Adenoviruses cause respiratory, gastrointestinal, and eye infections, including highly contagious viral pink eye. Some adenovirus eye infections lead to blindness. In patients with compromised immune systems, such as those infected with human immunodeficiency virus (HIV), an opportunistic adenovirus infection can be deadly.
The concept of blocking a viral protease is not, in itself, new. For instance, protease inhibitors have been among the most successful drugs in the struggle to treat patients infected with human immunodeficiency virus (HIV), the virus that causes AIDS, or acquired immunodeficiency syndrome. But, HIV is notorious for its ability to evolve resistant strains
The scientists, who already have two patents on the use of this enzyme, have begun looking for such drugs and hope to have the National Institutes of Health test some of them for anti-viral activity within a year.
