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Journal of Biological Chemistry

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Extracellular matrix proteins, Cell culture, Cell membranes, Cultures (Biology), Antiviral agents, Nucleic acids


The matrix (MA) domain of the HIV-1 PrGag protein directs PrGag proteins to assembly sites at the plasma membrane by virtue of its affinity to the phospholipid, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂). MA also binds to RNA at a site that overlaps its PI(4,5)P₂ site, suggesting that RNA binding may protect MA from associating with inappropriate cellular membranes prior to PrGag delivery to the PM. Based on this, we have developed an assay in which small molecule competitors to MA-RNA binding can be characterized, with the assumption that such compounds might interfere with essential MA functions and help elucidate additional features of MA binding. Following this approach, we have identified four compounds, including three thiadiazolanes, that compete with RNA for MA binding. We also have identified MA residues involved in thiadiazolane binding and found that they overlap the MA PI(4,5)P₂ and RNA sites. Cell culture studies demonstrated that thiadiazolanes inhibit HIV-1 replication, but are associated with significant levels of toxicity. Nevertheless, these observations provide new insights as to MA binding, and pave the way for the development of antivirals that target the HIV- 1 matrix domain.


Copyright © 2012, The American Society for Biochemistry and Molecular Biology. This instance is the author’s version of a work that was accepted for publication in The Journal of Biological Chemistry. Access the most updated version of this article at doi: 10.1074/jbc.M112.399865



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