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A possible new way to block HIV infection of healthy cells discovered

CHAMPAIGN, Ill. An experiment to understand how chemokine peptides dock to a receptor on a cell wall a pivotal connection that allows HIV to infect healthy cells has yielded an unexpected fundamental discovery and a possible new way to block AIDS.

There is still a lot to be done, but our findings provide new insights about the receptors flexibility and the potential mechanism of the interaction with HIV at the entry point of healthy cells, said Ziwei Huang, a professor of biochemistry at the University of Illinois at Urbana-Champaign.

Huang was the principal investigator of the study, which appears in the May 17 issue of the Journal of Biological Chemistry. Huangs team included researchers at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia and Dana-Farber Cancer Institute at the Harvard Medical School in Boston.

Researchers used computer modeling to predict the structure of chemokine receptor-ligand bonding. Then they synthesized reverse-chirality D-peptides, based on a portion of amino-acid sequences of two natural L-proteins that bond to CXCR4, a chemokine receptor to HIV discovered in the mid-1990s. CXCR4 and CD4, a receptor identifed in the 1980s, are thought to act together to let HIV bond and insert its replicating machinery into cells.

Only in rare cases and never involving membrane-class proteins have reverse-chirality peptides bound at identical receptors. We didnt have any expectation that our synthesized peptide would bind to the CXCR4 receptor, Huang said. If you switch the chirality, you have a mirror-image change. Youd expect a different lineup of key amino-acid sidechains. We looked at this out of pure curiosity. We just wanted to see what would happen.

Unexpectedly, he said, these D-peptides displayed strong binding and antagonistic activity toward CXCR4, thus revealing that the peptide binding site on CXCR4 is tolerant of changes in the chirality of ligands, Huang said. Normally, lig
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Contact: Jim Barlow
b-james3@uiuc.edu
217-333-5802
University of Illinois at Urbana-Champaign
15-May-2002


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