The human immunodeficiency virus type 1 (HIV-1) protease inhibitor UIC-PI (1) was developed via structure-based design and incorporated a novel bis-tetrahydrofuran (bis-THF) ligand in the (R)-(hydroxyethyl)sulfonamide based isostere. The EC(50) and EC(90) of the compound in acutely-infected H9 cells were <1 and approximately 1 nM, respectively. In chronically infected H9/HIV-1(IIIB) cells, the EC(50) and EC(90) were 20 and 50 nM, respectively. In parallel studies comparing UIC-PI and saquinavir in H9/HIV-1(IIIB) cells, viral p24 levels in culture supernatants were an order of magnitude lower with UIC-PI than with saquinavir.