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

Ayna Alfadhli, Henry McNett, Jacob Eccles, Seyram Tsagli, Colleen Noviello, Rachel Sloan, Claudia S. López, David H. Peyton, Eric Barklis

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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, phos-phatidylinositol-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 into MA binding and pave the way for the development of antivirals that target the HIV-1 matrix domain.

Original languageEnglish (US)
Pages (from-to)666-676
Number of pages11
JournalJournal of Biological Chemistry
Issue number1
StatePublished - Jan 4 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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