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

Target Protease

The target protein is an enzyme called a protease, which cleaves other proteins to complete the maturation of newly synthesized virus particles.

The structure of the adenovirus protease, with one cofactor in red and, in turquoise, the amino acids present in the active site.

Similar to the way supportive scaffolding is removed after the completion of a construction project, this protease cleaves, or cuts out, viral “construction” proteins, leaving infectious virus particles behind. Without the protease, the viruses cannot continue to produce infectious progeny. “If you can block the activity of this enzyme,” says Mangel, “then you can block the infection.”

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.

What is new in Mangel’s approach is the idea of using multiple drugs aimed at different sites on the same enzyme.

The idea arose from x-ray crystallography studies conducted by Mangel and others at the National Synchrotron Light Source (NSLS; see related story) at Brookhaven Lab. By shining the NSLS’s intense beam of x-rays on a crystal of a viral protease and recording how the x-rays scatter off the atoms in the sample, the scientists were able to produce a three-dimensional map of the protein’s molecular structure.

The protease they used was from adenovirus, which causes colds and pink eye. It has features in common, however, with proteases from many other viruses, including HIV, and some bacteria, such as those that cause Chlamydia and plague.

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