title: Analysis of small molecule ligands targeting the HIV-1 matrix protein-RNA binding site.
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.
authors.affiliation: Vollum Institute and Department of Microbiology, Oregon Health and Science University, Portland, Oregon 97201-3098, USA.
authors.forename: Ayna
authors.initials: A
authors.lastname: Alfadhli
authors.forename: Henry
authors.initials: H
authors.lastname: McNett
authors.forename: Jacob
authors.initials: J
authors.lastname: Eccles
authors.forename: Seyram
authors.initials: S
authors.lastname: Tsagli
authors.forename: Colleen
authors.initials: C
authors.lastname: Noviello
authors.forename: Rachel
authors.initials: R
authors.lastname: Sloan
authors.forename: Claudia S
authors.initials: CS
authors.lastname: López
authors.forename: David H
authors.initials: DH
authors.lastname: Peyton
authors.forename: Eric
authors.initials: E
authors.lastname: Barklis
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D002460:Cell Line; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015497:HIV-1 / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010743:Phospholipids / Q000737:chemistry*; D011485:Protein Binding; D012313:RNA / Q000737:chemistry*; D012190:Retroviridae / Q000378:metabolism; D013830:Thiadiazoles / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D008024:Ligands; D010743:Phospholipids; D013830:Thiadiazoles; D012313:RNA