Non-peptide entry inhibitors of HIV-1 that target the gp41 coiled coil pocket

  • Bioorg Med Chem Lett. 2010 Jan 15;20(2):612-7. doi: 10.1016/j.bmcl.2009.11.076.
Kent D Stewart  1 ,  Jeffrey R Huth ,  Teresa I Ng ,  Keith McDaniel ,  Rebecca Newlin Hutchinson ,  Vincent S Stoll ,  Renaldo R Mendoza ,  Edmund D Matayoshi ,  Robert Carrick ,  Hongmei Mo ,  Jean Severin ,  Karl Walter ,  Paul L Richardson ,  Leo W Barrett ,  Robert Meadows ,  Steve Anderson ,  William Kohlbrenner ,  Clarence Maring ,  Dale J Kempf ,  Akhter Molla ,  Edward T Olejniczak
Affiliations
  • 1. Pharmaceutical Discovery Division, Abbott Laboratories, 100 Abbott Park Rd., R46Y, AP10, Abbott Park, IL 60064-6098, United States. [email protected]
PMID: 20004576 DOI: 10.1016/j.bmcl.2009.11.076
Abstract

The ectodomain of HIV-1 gp41 mediates the fusion of viral and host cellular membranes. The peptide-based drug Enfuvirtide(1) is precedent that antagonists of this fusion activity may act as anti HIV-agents. Here, NMR screening was used to discover non-peptide leads against this target and resulted in the discovery of a new benzamide 1 series. This series is non-peptide, low molecular weight, and analogs have activity in a cell fusion assay with EC50 values ranging 3-41microM. Structural work on the gp41/benzamide 1 complex was determined by NMR spectroscopy using a designed model peptide system that mimics an open pocket of the fusogenic form of the protein.