NDLI: Analysis of small molecule ligands targeting the HIV-1 matrix protein-RNA binding site.

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Analysis of small molecule ligands targeting the HIV-1 matrix protein-RNA binding site.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Eccles, Jacob López, Claudia S. Tsagli, Seyram Peyton, David H. Barklis, Eric Noviello, Colleen Sloan, Rachel Alfadhli, Ayna Mcnett, Henry
Description	Author Affiliation: Alfadhli A ( Vollum Institute and Department of Microbiology, Oregon Health and Science University, Portland, Oregon 97201-3098, USA.)
Abstract	The matrix domain (MA) of the HIV-1 precursor Gag (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)P(2)). MA also binds to RNA at a site that overlaps its PI(4,5)P(2) 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)P(2) 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 into MA binding and pave the way for the development of antivirals that target the HIV-1 matrix domain.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	1
Volume Number	288
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2013-01-04
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Anti-HIV Agents Chemistry HIV-1 Ligands Phospholipids RNA Binding Sites Cell Line Cell Survival Dose-Response Relationship, Drug Drug Design Magnetic Resonance Spectroscopy Microscopy, Fluorescence Models, Chemical Models, Molecular Molecular Conformation Protein Binding Retroviridae Metabolism Thiadiazoles Research Support, N.I.H., Extramural Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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