BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1

BMS-232632 is an azapeptide human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor that displays potent anti-HIV-1 activity (50% effective concentration [EC 50 ], 2.6 to 5.3 nM; EC 90 , 9 to 15 nM). In vitro passage of HIV-1 RF in the presence of inhibitors showed that BMS-232632 selected for resistant variants more slowly than nelfinavir or ritonavir did. Genotypic and phenotypic analysis of three different HIV strains resistant to BMS-232632 indicated that an N88S substitution in the viral protease appeared first during the selection process in two of the three strains. An I84V change appeared to be an important substitution in the third strain used. Mutations were also observed at the protease cleavage sites following drug selection. The evolution to resistance seemed distinct for each of the three strains used, suggesting multiple pathways to resistance and the importance of the viral genetic background. A cross-resistance study involving five other protease inhibitors indicated that BMS-232632-resistant virus remained sensitive to saquinavir, while it showed various levels (0.1-to 71-fold decrease in sensitivity)-of cross-resistance to nelfinavir, indinavir, ritonavir, and amprenavir. In reciprocal experiments, the BMS-232632 susceptibility of HIV-1 variants selected in the presence of each of the other HIV-1 protease inhibitors showed that the nelfinavir-, saquinavir-, and amprenavir-resistant strains of HIV-1 remained sensitive to BMS-232632, while indinavir-and ritonavirresistant viruses displayed six-to ninefold changes in BMS-232632 sensitivity. Taken together, our data suggest that BMS-232632 may be a valuable protease inhibitor for use in combination therapy. , integrase, and Prt) (18). The Prt functions at the late stages of viral replication during virion maturation and has proved to be an effective target for antiviral intervention. Currently, five peptidic Prt inhibitors, saquinavir (SQV), indinavir (IDV), ritonavir (RTV), nelfinavir (NFV), and amprenavir (APV), are approved for clinical use (7,19,30,32,41). This class of drugs suppresses viral replication to a greater extent than the RT inhibitors in HIV-1-infected patients (12,13,24,25,27,28,42). Today, the standard care for AIDS patients involves the use of two RT inhibitors and one Prt inhibitor to reduce viremia to unquantifiable levels for an extended period of time (2, 13, 14, 27, 29; M. Markowitz, Y. Cao, A. Hurley, R. Schluger, S. Monard, R. Kost, B. Kerr, R. Anderson, S. Eastman, and D. D. Ho, 5th Conf. Retrovir. Opportunistic Infections, abstr. 371, 1998). Despite such a remarkable result, 30 to 50% of patients ultimately fail therapy, presumably due to patient nonadherence to drug schedules (as a consequence of inconvenient dosing and side effects) (43), insufficient drug exposure, and resistance development. Therefore, additional Prt inhibitors that display greater potency, improved bioavailability, fewer side effects, and distinct resistance profiles are needed.The emergence of resistant variants results from the larg...

A fungal metabolite, BMS-182123, which inhibited bacterial endotoxin-induced production of tumor necrosis factor (TNF-a) in murine macrophages and humanperipheral blood monocytes (in vitro), was isolated from the culture broth of Penicillium chrysogenumstrain V39673.The effective BMS-1 82123 concentration (IC50) resulting in 50% inhibition of lipopolysaccharide-induced TNF-a production in murine macrophages and humanmonocytes was 600 ng/ml and 4.0 jug/ml, respectively. BMS-182123 suppressed the lipopolysaccahride-induced TNF-a promoter activity and did not affect the stability of posttranscriptional mRNA. Addition of hydrophobic resin, Amberlite XAD-8(1 %), to the fermentation enhanced the production of BMS-182123by 5.5 fold. A total of 577mg pure BMS-182123 was recovered from a 250-liter fermentation supplemented with 1 %Amberlite XAD-8.

Atazanavir, which is marketed as REYATAZ, is the first human immunodeficiency virus type 1 (HIV-1) protease inhibitor approved for once-daily administration. As previously reported, atazanavir offers improved inhibitory profiles against several common variants of HIV-1 protease over those of the other peptidomimetic inhibitors currently on the market. This work describes the X-ray crystal structures of complexes of atazanavir with two HIV-1 protease variants, namely, (i) an enzyme optimized for resistance to autolysis and oxidation, referred to as the cleavage-resistant mutant (CRM); and (ii) the M46I/V82F/I84V/L90M mutant of the CRM enzyme, which is resistant to all approved HIV-1 protease inhibitors, referred to as the inhibitor-resistant mutant. In these two complexes, atazanavir adopts distinct bound conformations in response to the V82F substitution, which may explain why this substitution, at least in isolation, has yet to be selected in vitro or in the clinic. Because of its nearly symmetrical chemical structure, atazanavir is able to make several analogous contacts with each monomer of the biological dimer.The human immunodeficiency virus type 1 (HIV-1) protease (PRT) enzyme is essential for viral replication. As such, it is an attractive target for antiviral therapy. Indeed, a sustained, international effort of structure-based drug design has led to the development of potent HIV-1 PRT inhibitors (PIs) that bind to the active site of mature PRT. Several of these drugs are currently in use for the treatment of AIDS (18,31,36). The seven FDA-approved PIs currently on the market (in order of approval [http://www.fda.gov/oashi/aids/virals.html])-saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, and atazanavir-are competitive peptidomimetics (10,15). Unfortunately, the use of these PIs can lead to rapid selection for drug-resistant PRT variants (1,42,50). Mutations of the conserved PRT residues V82, I84, and L90 are among those most commonly observed in patients receiving PI-containing regimens. In addition, the collective data from clinical failures of antiviral therapy show considerable cross-resistance among the PIs (19). Both factors threaten the long-term effectiveness of these drugs. Therefore, it is important to understand the mechanisms that govern drug resistance in order to develop more effective inhibitors and to rationally formulate drug regimens.Atazanavir, a highly potent azapeptide, is the most recently approved HIV-1 PI. A favorable pharmacokinetic profile allows once-daily dosing (37,43,47). More importantly, atazanavir has a distinct resistance profile relative to those of the other approved PIs. Earlier in vitro studies demonstrated that the substitutions M46I, A71V, N88S, I84V, and I50L, which were identified in laboratory strains of PRT variants selected against atazanavir, may play important roles in the resistance phenotype and that multiple mutational pathways can lead to resistance (17). In clinical studies of treatment-experienced patients who received atazanavir-c...