AIDSWEEKLY Plus; Monday, May 23, 2005
Staff Medical Writers

"HIV-1 integrase (IN) is an important target for designing new antiviral therapies. Screening of potential inhibitors using recombinant IN-based assays has revealed a number of promising leads including nucleotide analogs such as pyridoxal 5'-phosphate (PLP). Certain PLP derivatives were shown to also exhibit antiviral activities in cell-based assays," researchers in the United States report.

"To identify an inhibitory binding site of PLP to IN," wrote scientists, "we used the intrinsic chemical property of this compound to form a Schiff base with a primary amine in the protein at the nucleotide binding site. The amino acid affected was then revealed by mass spectrometric analysis of the proteolytic peptide fragments of IN."

"We found that an IC50 concentration (15 muM) of PLP modified a single IN residue, Lys(244), located in the C-terminal domain. In fact," the authors continued, "we observed a correlation between interaction of PLP with Lys(244) and the compound's ability to impair formation of the IN.DNA complex."

"Site-directed mutagenesis studies confirmed an essential role of Lys(244) for catalytic activities of recombinant IN and viral replication," said K.L. Williams and coworkers at Ohio State University in Columbus.

Investigators concluded, "Molecular modeling revealed that Lys(244) together with several other DNA binding residues provides a plausible pocket for a nucleotide inhibitor-binding site.

"To our knowledge, this is the first report indicating that a small molecule inhibitor can impair IN activity through its binding to the protein C terminus. At the same time, our findings highlight the importance of structural analysis of the full-length protein."

Williams and colleagues published their study in the Journal of Biological Chemistry (Mass spectrometric analysis of the HIV-1 integrase-pyridoxal 5'-phosphate complex reveals a new binding site for a nucleotide inhibitor. J Biol Chem. 2005 Mar 4;280(9):7949-55.

For additional information, contact M. Kvaratskhelia, Ohio State University, College Pharmacy, Hlth Science Center, Center Retrovirus Research, 500 W 12th Avenue, Columbus, OH 43210, USA.

Publisher contact information for the Journal of Biological Chemistry is: American Society Biochemistry Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814-3996, USA.

Keywords: Columbus, Ohio, United States, HIV/AIDS, Integrase Inhibitor, Molecular Modeling, Binding Site, Pharmaceutical & Drug Development.

This article was prepared by AIDS Weekly editors from staff and other reports.

Reference

Williams KL, Zhang Y, Shkriabai N, et al. Mass spectrometric analysis of the HIV-1 integrase-pyridoxal 5'-phosphate complex reveals a new binding site for a nucleotide inhibitor, J Biol Chem. 2005 Mar 4;280(9):7949-55.

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