In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV

Abstract

Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC 50 s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC 50 s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC 50 s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro.

In Vitro Characterization of GS-8374, a Novel Phosphonate-Containing Inhibitor of HIV-1 Protease with a Favorable Resistance Profile

“…It should be kept in mind that compounds with various P-1 phenyl substitutions have been previously described. One such example is brecanavir (GW-0385), a highly potent PI with a resistance profile superior to that of darunavir that has reached phase 2 clinical evaluation (11). Brecanavir contains a methylthiazole substitution of the P-1 phenyl residue, and although both the para position and the methoxy linker are same as in GS-8374, the resistance profile of brecanavir is less favorable (see Fig.…”

Pharmacovirological Impact of an Integrase Inhibitor on Human Immunodeficiency Virus Type 1 cDNA Species In Vivo

“…EC 50 s were determined by using Prism software (GraphPad, San Diego, CA) and are shown in panels B to E and in Table 3. H-INI binding, and antiviral HIV activity in cell-based assays were measured as reported previously (5,14,25). The values are geometric means, with 95% CI in parentheses, calculated from at least seven determinations.…”

“…In vitro recombinant HIV IN strand transfer activity (5) and INI binding (14) were measured as previously described. Antiviral HIV activity was measured in human MT-4 T cells as reported previously (14,25). HIV-1 Ba-L replication in PBMCs was quantitated by measuring reverse transcriptase activity present in the supernatant (25).…”

Blockade of X4-Tropic HIV-1 Cellular Entry by GSK812397, a Potent Noncompetitive CXCR4 Receptor Antagonist

“…HIV-1 IIIB replication in PBMCs was quantified by measuring reverse transcriptase (RT) activity present in the supernatant as previously described (7). PHA-stimulated PBMCs were pelleted at 260 ϫ g for 15 min, washed once with sterile phosphate-buffered saline, pelleted as described above, and resuspended to a density of 4 ϫ 10 6 cells/ml in RPMI 1640 medium containing 20% FCS, 10% IL-2, and 50 g/ml gentamicin.…”