bms-488043 and HIV-Infections

Attachment inhibitors (AI) are a novel class of HIV-1 antivirals, with little information available on clinical resistance. BMS-488043 is an orally bioavailable AI that binds to gp120 of HIV-1 and abrogates its binding to CD4(+) lymphocytes. A clinical proof-of-concept study of the AI BMS-488043, administered as monotherapy for 8 days, demonstrated significant viral load reductions. In order to examine the effects of AI monotherapy on HIV-1 sensitivity, phenotypic sensitivity assessment of baseline and postdosing (day 8) samples was performed. These analyses revealed that four subjects had emergent phenotypic resistance (a 50% effective concentration [EC(50)] >10-fold greater than the baseline value) and four had high baseline EC(50)s (>200 nM). Population sequencing and sequence determination of cloned envelope genes uncovered five gp120 mutations at four loci (V68A, L116I, S375I/N, and M426L) associated with BMS-488043 resistance. Substitution at the 375 locus, located near the CD4 binding pocket, was the most common (maintained in 5/8 subjects at day 8). The five substitutions were evaluated for their effects on AI sensitivity through reverse genetics in functional envelopes, confirming their role in decreasing sensitivity to the drug. Additional analyses revealed that these substitutions did not alter sensitivity to other HIV-1 entry inhibitors. Thus, our studies demonstrate that although the majority of the subjects' viruses maintained sensitivity to BMS-488043, substitutions can be selected that decrease HIV-1 susceptibility to the AI. Most importantly, the substitutions described here are not associated with resistance to other approved antiretrovirals, and therefore, attachment inhibitors could complement the current arsenal of anti-HIV agents.

Topics: Amino Acid Sequence; Anti-HIV Agents; CD4 Antigens; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Viral; HIV Envelope Protein gp120; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Indoles; Microbial Sensitivity Tests; Models, Molecular; Molecular Sequence Data; Piperazines; Polymerase Chain Reaction; Pyruvic Acid; Sequence Analysis, DNA; Treatment Outcome

BMS-488043 is a novel and unique oral small-molecule inhibitor of the attachment of human immunodeficiency virus type 1 (HIV-1) to CD4(+) lymphocytes. The antiviral activity, pharmacokinetics, viral susceptibility, and safety of BMS-488043 were evaluated in an 8-day monotherapy trial. Thirty HIV-1-infected study subjects were randomly assigned to sequential, safety-guided dose panels of 800 and 1,800 mg BMS-488043 or a matched placebo in a 4:1 ratio, and the drug was administered every 12 h with a high-fat meal for 7 days and on the morning of day 8. Dose-related, albeit less-than-dose-proportional, increases in plasma BMS-488043 concentrations were observed. Mean plasma HIV-1 RNA decreases from the baseline for the BMS-488043 800- and 1,800-mg dose groups on day 8 were 0.72 and 0.96 log(10) copies/ml, respectively, compared with 0.02 log(10) copies/ml for the placebo group. A lower baseline BMS-488043 50% effective concentration (EC(50)) in the active-treatment groups was predictive of a greater antiviral response. Although absolute drug exposure was not associated with an antiviral response, the trough concentration (C(trough)), adjusted by the baseline EC(50) (C(trough)/EC(50)), was associated with antiviral activity. During dosing, four subjects experienced >10-fold reductions in viral susceptibility to BMS-488043, providing further support of the direct antiviral mechanism of BMS-488043. BMS-488043 was generally safe and well tolerated. These results suggest that further development of this novel class of oral HIV-1 attachment inhibitors is warranted.

Topics: Administration, Oral; Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Indoles; Male; Microbial Sensitivity Tests; Middle Aged; Piperazines; Pyruvic Acid; RNA, Viral; Treatment Outcome; Viral Load

A recently discovered small-molecule inhibitor, BMS-488043 (BMS-488), for the invasion of Human immunodeficiency virus Type 1 (HIV-1), shows a high activity against the entry of diversified HIV-1. Docking and molecular dynamic studies have been carried out to understand the binding mode of BMS-488 to gp120 as well as the effect of the small molecule on the conformational change of gp120 induced by CD4 binding. The results indicate that BMS-488 can accommodate in the CD4 binding pocket and interfere the CD4 binding in a noncompetitive mode. The piperazine group of BMS-488 prevents the bridging sheet formation of gp120 induced by the CD4 binding mainly through blocking the rotation of the Trp112 located on the α1 helix of gp120. The bridging sheet formation cannot be blocked for the W112A mutant of gp120 due to the reduced steric hindrance, in agreement with its significant resistance to the BMS inhibitor. The aza-indole ring is likely to interfere the exposure of gp41 by stacking within the β3-β5 and LB loops to disrupt the close packing of Pro212-His66-Phe210. The mode of action of BMS-488 also accommodates many mutagenesis results related to BMS-488 activity.

Topics: CD4 Antigens; HIV Envelope Protein gp120; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Indoles; Molecular Dynamics Simulation; Piperazines; Protein Binding; Protein Conformation; Pyruvic Acid; Virus Internalization

Treatment with HIV attachment inhibitors (AIs) can select for escape mutants throughout the viral envelope. We report on three such mutations: F423Y (gp120 CD4 binding pocket) and I595F and K655E (gp41 ectodomain). Each displayed decreased sensitivity to the AI BMS-488043 and earlier generation AIs, along with increased sensitivity to the broadly neutralizing antibodies 2F5 and 4E10, without affecting the rate of viral entry or sensitivity to the entry inhibitors AMD-3100 and Enfuvirtide. We also observed that I595F did not substantially increase envelope sensitivity to HIV-infected patient sera. Based on these observations, we propose that although F423Y, I595F and K655E may all affect the presentation of the 2F5 and 4E10 epitopes, natural immune mimicry is rare only for the I595F effect. Thus, it seems that in addition to restricting AI resistance development, incorporation of I595F into an appropriate vehicle could elicit a novel antiviral response to improve vaccine efficacy.

Topics: Antibodies, Neutralizing; Drug Resistance, Viral; HIV Antibodies; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Indoles; Molecular Structure; Mutation, Missense; Neutralization Tests; Piperazines; Pyruvic Acid

Azaindole derivatives derived from the screening lead 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (1) were prepared and characterized to assess their potential as inhibitors of HIV-1 attachment. Systematic replacement of each of the unfused carbon atoms in the phenyl ring of the indole moiety by a nitrogen atom provided four different azaindole derivatives that displayed a clear SAR for antiviral activity and all of which displayed marked improvements in pharmaceutical properties. Optimization of these azaindole leads resulted in the identification of two compounds that were advanced to clinical studies: (R)-1-(4-benzoyl-2-methylpiperazin-1-yl)-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione (BMS-377806, 3) and 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione (BMS-488043, 4). In a preliminary clinical study, 4 administered as monotherapy for 8 days, reduced viremia in HIV-1-infected subjects, providing proof of concept for this mechanistic class.

Topics: Animals; Anti-HIV Agents; Cell Line; Drug Discovery; HIV Infections; HIV-1; Humans; Indoles; Models, Molecular; Molecular Conformation; Piperazines; Pyruvic Acid; Rats; Reproducibility of Results; Virus Attachment