In her HIV model, Chmielewski targeted a site where identical pieces on two proteins come together to form what is called a "dimer." The dimer then becomes an essential enzyme, prompting numerous chemical reactions that allow the virus to replicate.
"This particular enzyme is only active when those two identical pieces join together, so if we can stop the proteins from coming together, we may be able to put the brakes on the replication process," Chmielewski says.
That fact has not escaped drug companies in the last decade. The Food and Drug Administration has approved a number of compounds to target this particular enzyme. But the sites on the virus where those compounds work can mutate fairly easily, making the drugs resistant with time, Chmielewski says.
She says the new approach may help prevent the possibility of drug resistance because it acts on a site that is less likely to mutate.
"We think this might be a way to get in the back door and eliminate or reduce the problem of mutations and the possibility of drug resistance," she says.
The "wedge" molecules were developed by taking pieces of the most active sites on the identical protein segments and putting them into one molecule. After developing a prototype molecule, Chmielewski and her group worked to make smaller and smaller versions of it to obtain an agent small enough to pass through a cell's membrane. The group then developed different versions of the molecule, producing a small library of different compounds.
Chmielewski is now working with collaborators at NIH to test a dozen of those compounds in cells infected with HIV. If the approach proves successful, it may be developed further and carried into human trials within the next five years.
The use of molecular wedges may someday also provide a radical
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Contact: Susan Gaidos
sgaidos@uns.purdue.edu
765-494-2081
Purdue University
19-Aug-2000