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New Approach to Anti-Viral Therapy May Help Overcome Drug Resistance

Co-Factor Interaction

Other studies by Mangel’s group indicated that, in order for the adenovirus protease to be active, it must interact with several different co-factors. The x-ray technique allowed the scientists to identify the sites where the various co-factors bind to the enzyme, and the subsequent sequence of structural changes occurring between these sites that leads to the activation of the protease.

A small molecular weight drug (top, left and right) was predicted by a computer program to bind to the adenovirus protease (yellow) active site (green and turquoise). The drug is shown binding to the active site (bottom, right).

One very significant finding is that different parts of the enzyme interact with one another.

One of the co-factors, for example, binds to a site on the enzyme that is quite far from the active site — the part of the protease involved in cleaving protein. Yet, its binding produces structural changes in the active site. Its binding also produces structural changes in the binding site of another co-factor, which also attaches far from the active site. Thus, these crucial sites interact with each other.

These structural details all give the scientists a variety of targets against which to design drugs that can interfere with the active site, the co-factor binding sites, or the pathways between these sites along which signals are transmitted to produce the structural changes. The idea behind such structure-based drug design is to select small molecules that will fit into the structural nooks and crannies important to the functioning of the enzyme. The process is helped along by a powerful computer program that searches databases containing the structures of millions of small molecules, looking for ones that fit.

“Certain viruses have learned how to survive most any challenge in the environment, including the presence of anti-viral drugs. One of the biggest challenges to modern biology is to find ways to thwart them.”
--Walter Mangel

Using this approach, Mangel's team has already developed five potential drug candidates that block the active site of the adenovirus protease. Once characterized, these drugs will be tested by the NIH to see if they act as anti-viral agents.

Multiple Targets

The next step will be to design drugs that block parts of the protease-activation sequence. A drug designed to block any part of this sequence could disable the viral enzyme. As Mangel explains: “The protease-activation sequence can be viewed as a road, so a drug that blocks anywhere along the road prevents the activation sequence from being completed.”

Disabling this pathway is particularly appealing because the interconnectedness of the steps makes it much harder for the virus to evolve resistance to the drugs. Why? Because any mutation in the virus protease that destroys a drug’s effectiveness might also change some other part of the enzyme’s structure in a way that disrupts the enzyme-activation sequence. Such changes would not be selected for because, without an active protease, the virus would be unable to pass on the drug-resistant trait to new virus particles.

“Using multiple drugs targeted at multiple sites along this sequence would be most effective of all,” says Mangel, “because the likelihood of resistance evolving to multiple drugs without altering the crucial activation sequence is infinitely small.”

 
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