Li Fan

Bristol-Myers Squibb, New York, New York, United States

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Publications (7)32.4 Total impact

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    ABSTRACT: In an 8 day monotherapy study of subjects infected with HIV-1 (subtype B) (NCT01009814), BMS-626529 (an attachment inhibitor that binds to HIV-1 envelope glycoprotein gp120), administered as the prodrug BMS-663068, produced substantial declines in plasma HIV-1 RNA. However, large variability in susceptibility to BMS-626529 was noted and virus with low susceptibility was less likely to be suppressed by BMS-663068 administration. The current analysis sought to investigate the genotypic correlates of susceptibility to BMS-626529. In vitro selection experiments, evaluation of clinical samples of subtype B from the monotherapy study and evaluation of intrinsically resistant subtype AE viruses were conducted. Reverse genetics was used to identify key substitutions in envelope clones responsible for reduced susceptibility. An M426L or S375M change were the major substitutions associated with reductions in susceptibility to BMS-626529 in baseline samples of subtype B viruses from the monotherapy study, with M434I and M475I contributing to a lesser extent. Class resistance in subtype AE viruses was mapped to 375H and 475I substitutions, found in the vast majority of these viruses. Analysis of multiple envelope clones from infected subjects showed higher intrasubject variability in susceptibility to BMS-626529 compared with other classes of entry inhibitors. These data define key genotypic substitutions in HIV-1 gp120 that could confer phenotypic resistance to BMS-626529.
    Journal of Antimicrobial Chemotherapy 10/2013; 69(3). DOI:10.1093/jac/dkt412 · 5.44 Impact Factor
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    ABSTRACT: 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.
    Antimicrobial Agents and Chemotherapy 11/2010; 55(2):729-37. DOI:10.1128/AAC.01173-10 · 4.45 Impact Factor
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    ABSTRACT: 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.
    Virology 07/2010; 402(2):256-61. DOI:10.1016/j.virol.2010.03.033 · 3.28 Impact Factor
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    ABSTRACT: 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.
    Journal of Medicinal Chemistry 09/2009; 52(23):7778-87. DOI:10.1021/jm900843g · 5.48 Impact Factor
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    ABSTRACT: Entecavir (ETV) was developed for the treatment of chronic hepatitis B virus (HBV) infection and is globally approved for that indication. Initial preclinical studies indicated that ETV had no significant activity against human immunodeficiency virus type 1 (HIV-1) in cultured cell lines at physiologically relevant ETV concentrations, using traditional anti-HIV assays. In response to recent clinical observations of anti-HIV activity of ETV in HIV/HBV-coinfected patients not receiving highly active antiretroviral therapy (HAART), additional investigative studies were conducted to expand upon earlier results. An extended panel of HIV-1 laboratory and clinical strains and cell types was tested against ETV, along with a comparison of assay methodologies and resistance profiling. These latest studies confirmed that ETV has only weak activity against HIV, using established assay systems. However, a >100-fold enhancement of antiviral activity (equivalent to the antiviral activity of lamivudine) could be obtained when assay conditions were modified to reduce the initial viral challenge. Also, the selection of a M184I virus variant during the passage of HIV-1 at high concentrations of ETV confirmed that ETV can exert inhibitory pressure on the virus. These findings may have a significant impact on how future assays are performed with compounds to be used in patients infected with HIV. These results support the recommendation that ETV therapy should be administered in concert with HAART for HIV/HBV-coinfected patients.
    Antimicrobial Agents and Chemotherapy 06/2008; 52(5):1759-67. DOI:10.1128/AAC.01313-07 · 4.45 Impact Factor
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    ABSTRACT: BMS-488043 is a small-molecule human immunodeficiency virus type 1 (HIV-1) CD4 attachment inhibitor with demonstrated clinical efficacy. The compound inhibits soluble CD4 (sCD4) binding to the 11 distinct HIV envelope gp120 proteins surveyed. Binding of BMS-488043 and that of sCD4 to gp120 are mutually exclusive, since increased concentrations of one can completely block the binding of the other without affecting the maximal gp120 binding capacity. Similarly, BMS-488043 inhibited virion envelope trimers from binding to sCD4-immunoglobulin G (IgG), with decreasing inhibition as the sCD4-IgG concentration increased, and BMS-488043 blocked the sCD4-induced exposure of the gp41 groove in virions. In both virion binding assays, BMS-488043 was active only when added prior to sCD4. Collectively, these results indicate that obstruction of gp120-sCD4 interactions is the primary inhibition mechanism of this compound and that compound interaction with envelope must precede CD4 binding. By three independent approaches, BMS-488043 was further shown to induce conformational changes within gp120 in both the CD4 and CCR5 binding regions. These changes likely prevent gp120-CD4 interactions and downstream entry events. However, BMS-488043 could only partially inhibit CD4 binding to an HIV variant containing a specific envelope truncation and altered gp120 conformation, despite effectively inhibiting the pseudotyped virus infection. Taken together, BMS-488043 inhibits viral entry primarily through altering the envelope conformation and preventing CD4 binding, and other downstream entry events could also be inhibited as a result of these induced conformational changes.
    Journal of Virology 05/2006; 80(8):4017-25. DOI:10.1128/JVI.80.8.4017-4025.2006 · 4.65 Impact Factor
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    ABSTRACT: BMS-378806 is a recently discovered small-molecule human immunodeficiency virus type 1 (HIV-1) attachment inhibitor with good antiviral activity and pharmacokinetic properties. Here, we demonstrate that the compound targets viral entry by inhibiting the binding of the HIV-1 envelope gp120 protein to cellular CD4 receptors via a specific and competitive mechanism. BMS-378806 binds directly to gp120 at a stoichiometry of approximately 1:1, with a binding affinity similar to that of soluble CD4. The potential BMS-378806 target site was localized to a specific region within the CD4 binding pocket of gp120 by using HIV-1 gp120 variants carrying either compound-selected resistant substitutions or gp120-CD4 contact site mutations. Mapping of resistance substitutions to the HIV-1 envelope, and the lack of compound activity against a CD4-independent viral infection confirm the gp120-CD4 interactions as the target in infected cells. BMS-378806 therefore serves as a prototype for this new class of antiretroviral agents and validates gp120 as a viable target for small-molecule inhibitors.
    Journal of Virology 11/2003; 77(19):10528-36. DOI:10.1128/JVI.77.19.10528-10536.2003 · 4.65 Impact Factor