Session 66Poster Presentations New Antiretrovirals Session Day and Time: Tuesday 1:30 - 3:30 pm Room: Hall A
553 TMC114 (UIC96017): A Novel Nonpeptidic Protease Inhibitor Potent Against Multi-PI Resistant HIV In Vitro Y Koh*1, H Nakata1, K Maeda1, JF Kincaid2, G Bilcer2, D Thippeswamy2, AK Ghosh2, H Mitsuya1,3 1Kumamoto Univ Sch of Med, Japan; 2Univ of Illinois at Chicago; and 3Natl Cancer Inst, Bethesda, MD
Background: The rapid rise of multi-protease inhibitor (PI)-resistant HIV variants urges the development of new classes of PIs which are potent against existing resistant HIV variants and do not allow or delay the emergence of resistance. We designed, synthesized, and identified TMC114 (UIC96017), a novel non-peptidic PI containing 3(R), 3a(S), 6a(R)-bis-tetrahydrofuranyl urethane (bis-THF) and a sulfonamide isostere, which exerts potent activity against a wide spectrum of HIV including multi-drug resistant HIV variants (HIVMDR).
Methods: The inhibitor was synthesized in a convergent manner by coupling optically active P2-bis-THF ligand and (R)-(hydroxyethylamino) sulfonamide isostere. Antiviral activity of the compound against various HIVMDR was determined using MTT assay employing MT-2 cells and p24 assay using PHA-stimulated PBM and MT-4 cells. PI-resistant HIV variants were selected in vitro by propagating HIV in the presence of increasing concentrations of each of existing PIs including saquinavir, indinavir, nelfinavir, ritonavir, and amprenavir.
Results: TMC114 was identified to be extremely potent against various laboratory HIV strains and primary clinical isolates (IC50: ~0.003 microM) with minimal cytotoxicity (CC50: 74 microM) when tested in CD4+ MT-2 cells. TMC114, at relatively low concentrations (IC50: 0.003-0.03 microM), blocked the infection and replication of each of HIV-1NL4-3 variants exposed to and selected by up to 5 microM of saquinavir, indinavir, nelfinavir, or ritonavir, although it was less active to HIV-1NL4-3 selected by amprenavir (IC50: 0.28 microM). TMC114 was also potent (IC50 values ranging 0.003 to 0.031 microM) against multi-PI-resistant clinical HIV-1 variants, isolated from patients who had no response to any existing antiviral regimens after having received a variety of antiviral agents. Structural analysis revealed that the close contact of TMC114 with the main chains of the protease active site amino acids (Asp29 and Asp30) differed from that of other PIs and was thought to be important for its potency and activity against a wide spectrum of HIVMDR. When selected against TMC114 in vitro, HIV-1NL4-3 hardly acquired resistance to the drug. Pharmacokinetic analyses have revealed that TMC114 has favorable oral bio-availability.
Conclusions: These data warrant that TMC114 (UIC96017) be further developed as a potential therapeutic agent for treatment of infection with primary HIV and HIVMDR.
