scholarly journals TAK-220, a Novel Small-Molecule CCR5 Antagonist, Has Favorable Anti-Human Immunodeficiency Virus Interactions with Other Antiretrovirals In Vitro

2005 ◽  
Vol 49 (8) ◽  
pp. 3483-3485 ◽  
Author(s):  
Cécile L. Tremblay ◽  
Françoise Giguel ◽  
Yongbiao Guan ◽  
Ting-Chao Chou ◽  
Katsunori Takashima ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Ccr5 Antagonist ◽  
Entry Inhibitors ◽  
New Class ◽  
Immunodeficiency Virus ◽  
Virus Interactions ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT TAK-220 is a CCR5 antagonist, part of the new class of anti-human immunodeficiency virus type 1 (anti-HIV-1) entry inhibitors. We evaluated the anti-HIV-1 interactions between TAK-220 and various antiretrovirals in vitro. Synergy was observed with all drugs at the 90 and 95% inhibitory concentrations. The favorable drug interactions observed suggest that further clinical evaluation is warranted.

scholarly journals Mechanism of Action and In Vitro Activity of 1′,3′-Dioxolanylpurine Nucleoside Analogues against Sensitive and Drug-Resistant Human Immunodeficiency Virus Type 1 Variants

1999 ◽  
Vol 43 (10) ◽  
pp. 2376-2382 ◽  
Author(s):  
Zhengxian Gu ◽  
Mark A. Wainberg ◽  
Nghe Nguyen-Ba ◽  
Lucille L’Heureux ◽  
Jean-Marc de Muys ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Nucleoside Analogues ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT (−)-β-d-1′,3′-Dioxolane guanosine (DXG) and 2,6-diaminopurine (DAPD) dioxolanyl nucleoside analogues have been reported to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1). We have recently conducted experiments to more fully characterize their in vitro anti-HIV-1 profiles. Antiviral assays performed in cell culture systems determined that DXG had 50% effective concentrations of 0.046 and 0.085 μM when evaluated against HIV-1IIIB in cord blood mononuclear cells and MT-2 cells, respectively. These values indicate that DXG is approximately equipotent to 2′,3′-dideoxy-3′-thiacytidine (3TC) but 5- to 10-fold less potent than 3′-azido-2′,3′-dideoxythymidine (AZT) in the two cell systems tested. At the same time, DAPD was approximately 5- to 20-fold less active than DXG in the anti-HIV-1 assays. When recombinant or clinical variants of HIV-1 were used to assess the efficacy of the purine nucleoside analogues against drug-resistant HIV-1, it was observed that AZT-resistant virus remained sensitive to DXG and DAPD. Virus harboring a mutation(s) which conferred decreased sensitivity to 3TC, 2′,3′-dideoxyinosine, and 2′,3′-dideoxycytidine, such as a 65R, 74V, or 184V mutation in the viral reverse transcriptase (RT), exhibited a two- to fivefold-decreased susceptibility to DXG or DAPD. When nonnucleoside RT inhibitor-resistant and protease inhibitor-resistant viruses were tested, no change in virus sensitivity to DXG or DAPD was observed. In vitro drug combination assays indicated that DXG had synergistic antiviral effects when used in combination with AZT, 3TC, or nevirapine. In cellular toxicity analyses, DXG and DAPD had 50% cytotoxic concentrations of greater than 500 μM when tested in peripheral blood mononuclear cells and a variety of human tumor and normal cell lines. The triphosphate form of DXG competed with the natural nucleotide substrates and acted as a chain terminator of the nascent DNA. These data suggest that DXG triphosphate may be the active intracellular metabolite, consistent with the mechanism by which other nucleoside analogues inhibit HIV-1 replication. Our results suggest that the use of DXG and DAPD as therapeutic agents for HIV-1 infection should be explored.

An Approach towards the Synthesis of Potential Metal-Chelating TSAO-T Derivatives as Bidentate Inhibitors of Human Immunodeficiency virus Type 1 Reverse Transcriptase

1998 ◽  
Vol 9 (5) ◽  
pp. 412-421 ◽  
Author(s):  
C Chamorro ◽  
M-J Camarasa ◽  
M-J Pérez-Pérez ◽  
E de Clercq ◽  
J Balzarini ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Parent Compound ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Novel derivatives of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-T have been designed, synthesized and tested for their in vitro antiretro-viral activity against HIV. These TSAO-T derivatives have been designed as potential bidentate inhibitors of HIV-1 RT, which combine in their structure the functionality of a non-nucleoside RT inhibitor (TSAO-T) and a bivalent ion-chelating moiety (a β-diketone moiety) linked through an appropriate spacer to the N-3 of thymine of TSAO-T . Some of the new compounds have an anti-HIV-1 activity comparable to that of the parent compound TSAO-T, but display a markedly increased antiviral selectivity. There was a clear relationship between antiviral activity and the length of the spacer group that links the TSAO molecule with the chelating moiety. A shorter spacer invariably resulted in increased antiviral potency. None of the TSAO-T derivatives were endowed with anti-HIV-2 activity.

scholarly journals Inhibition of Human Immunodeficiency Virus by a New Class of Pyridine Oxide Derivatives

2003 ◽  
Vol 47 (9) ◽  
pp. 2951-2957 ◽  
Author(s):  
Miguel Stevens ◽  
Christophe Pannecouque ◽  
Erik De Clercq ◽  
Jan Balzarini
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Cell Cultures ◽  
New Class ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Immunodeficiency Virus ◽  
Amino Acid Mutations ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT A new class of pyridine oxide derivatives as inhibitors of human immunodeficiency virus type 1 (HIV-1) and/or HIV-2 replication in cell culture has been identified. The compounds, which specifically inhibit HIV-1, behave as typical nonnucleoside reverse transcriptase inhibitors (NNRTIs). The most active congener of this group, JPL-133 (UC-B3096), has a 50% effective concentration of 0.05 μg/ml for HIV-1(IIIB) with a selectivity index of approximately 760 in CEM cell cultures. However, the cytostatic activity of most pyridine oxide derivatives highly depended on the nature of the cell line. All compounds, including those pyridine oxide derivatives that inhibit both HIV-1 and HIV-2 replication, select for NNRTI-characteristic mutations in the HIV-1 reverse transcriptase of HIV-infected cell cultures (i.e., Lys103Asn, Val108Ile, Glu138Lys, Tyr181Cys and Tyr188His). These amino acid mutations emerged mostly through transition of guanine to adenine or adenine to guanine in the corresponding codons of the reverse transcriptase (RT) gene. The HIV-1-specific pyridine oxide derivatives lost their antiviral activity against HIV-1 strains containing these mutations in the RT. However, most compounds retained pronounced antiviral potency against virus strains that contained other NNRTI-characteristic RT mutations, such as Leu100Ile and Val179Asp. Furthermore, the complete lack of inhibitory activity of the pyridine oxide derivatives against recombinant HIV-2 RT and partial retention of anti-HIV-1 activity against HIV-1 strains that contain a variety of HIV-1-characteristic mutations suggest that the pyridine oxide derivatives must have a second target of antiviral action independent from HIV-1 RT.

scholarly journals 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

2007 ◽  
Vol 51 (9) ◽  
pp. 3147-3154 ◽  
Author(s):  
Richard Hazen ◽  
Robert Harvey ◽  
Robert Ferris ◽  
Charles Craig ◽  
Phillip Yates ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Protease Inhibitor ◽  
Reverse Transcriptase ◽  
In Vitro Assays ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

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 (EC50s) 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 EC50s. 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 EC50s 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.

scholarly journals Betulinic Acid Derivatives That Target gp120 and Inhibit Multiple Genetic Subtypes of Human Immunodeficiency Virus Type 1

2007 ◽  
Vol 52 (1) ◽  
pp. 128-136 ◽  
Author(s):  
Weihong Lai ◽  
Li Huang ◽  
Phong Ho ◽  
Zhijun Li ◽  
David Montefiori ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Broad Spectrum ◽  
Betulinic Acid ◽  
V3 Loop ◽  
Entry Inhibitors ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Betulinic acid (BA) derivatives can inhibit human immunodeficiency virus type 1 (HIV-1) entry or maturation depending on side chain modifications. While BA derivatives with antimaturation activity have attracted considerable interest, the anti-HIV-1 profile and molecular mechanism of BA derivatives with anti-HIV-1 entry activity (termed BA entry inhibitors) have not been well defined. In this study, we have found that two BA entry inhibitors, IC9564 and A43D, exhibited a broad spectrum of anti-HIV-1 activity. Both compounds inhibited multiple strains of HIV-1 from clades A, B, and C at submicromolar concentrations. Clade C viruses were more sensitive to the compounds than clade A and B viruses. Interestingly, IC9564 at subinhibitory concentrations could alter the antifusion activities of other entry inhibitors. IC9564 was especially potent in increasing the sensitivity of HIV-1YU2 Env-mediated membrane fusion to the CCR5 inhibitor TAK-779. Results from this study suggest that the V3 loop of gp120 is a critical determinant for the anti-HIV-1 activity of IC9564. IC9564 escape viruses contained mutations near the tip of the V3 loop. Moreover, IC9564 could compete with the binding of V3 monoclonal antibodies 447-52D and 39F. IC9564 also competed with the binding of gp120/CD4 complexes to chemokine receptors. In summary, these results suggest that BA entry inhibitors can potently inhibit a broad spectrum of primary HIV-1 isolates by targeting the V3 loop of gp120.

Synthesis and in vitro anti-HIV-1 activity of a series of N-arylsulfonyl-3-propionylindoles

2016 ◽  
Vol 71 (5-6) ◽  
pp. 105-109 ◽  
Author(s):  
Zhiping Che ◽  
Yuee Tian ◽  
Zhenjie Hu ◽  
Yingwu Chen ◽  
Shengming Liu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Therapeutic Index ◽  
Effective Concentration ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Abstract Fifteen N-arylsulfonyl-3-propionylindoles (3a–o) were prepared and preliminarily evaluated as in vitro inhibitors of human immunodeficiency virus type-1 (HIV-1). Three compounds 3c, 3g and 3i exhibited potent anti-HIV-1 activity with effective concentration (EC50) values of 0.8, 4.0 and 1.2 μg/mL, and therapeutic index (TI) values of 11.7, 16.6 and 84.1, respectively. N-(m-Nitro)phenylsulfonyl-3-propionyl-6-methylindole (3i) exhibited the most promising and best activity against HIV-1 replication. The cytotoxicity of these compounds was assessed as well.

scholarly journals Restoration of Anti-Human Immunodeficiency Virus Type 1 (HIV-1) Responses in CD8+ T Cells from Late-Stage Patients on Prolonged Antiretroviral Therapy by Stimulation In Vitro with HIV-1 Protein-Loaded Dendritic Cells

2001 ◽  
Vol 75 (9) ◽  
pp. 4413-4419 ◽  
Author(s):  
Zheng Fan ◽  
Xiao-Li Huang ◽  
Luann Borowski ◽  
John W. Mellors ◽  
Charles R. Rinaldo
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Antiretroviral Therapy ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We demonstrate that dendritic cells loaded in vitro with human immunodeficiency virus type 1 (HIV-1) protein-liposome complexes activate HLA class I-restricted anti-HIV-1 cytotoxic T-lymphocyte and gamma interferon (IFN-γ) responses in autologous CD8+ T cells from late-stage HIV-1-infected patients on prolonged combination drug therapy. Interleukin-12 enhanced this effect through an interleukin-2- and IFN-γ-mediated pathway. This suggests that dendritic cells from HIV-1-infected persons can be engineered to evoke stronger anti-HIV-1 CD8+ T-cell reactivity as a strategy to augment antiretroviral therapy.

scholarly journals Characterization of Human Class-Switched Polymeric (Immunoglobulin M [IgM] and IgA) Anti-Human Immunodeficiency Virus Type 1 Antibodies 2F5 and 2G12

2003 ◽  
Vol 77 (7) ◽  
pp. 4095-4103 ◽  
Author(s):  
Susanne Wolbank ◽  
Renate Kunert ◽  
Gabriela Stiegler ◽  
Hermann Katinger
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunoglobulin M ◽  
Mucosal Transmission ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We have previously generated human monoclonal anti-human immunodeficiency virus type 1 (anti-HIV-1) antibodies 2F5IgG and 2G12IgG with an exceptional cross-clade neutralizing potential. 2F5IgG and 2G12IgG passively administrated to macaques were able to confer complete protection from both intravenous and mucosal challenge with pathogenic HIV-simian immunodeficiency virus chimeric strains and have shown beneficial effects in a phase-1 clinical trial. We now class-switched 2F5 and 2G12 to the immunoglobulin M (IgM) or IgA isotype, to enforce features like avidity, complement activation, or the potential to neutralize mucosal transmission. For this purpose we expressed functional polymeric 2F5 and 2G12 antibodies in CHO cells and evaluated their anti-HIV-1 activity in vitro. The class switch had a strong impact on the protective potential of 2F5 and 2G12. 2G12IgM inhibited HIV-1 infection of peripheral blood mononuclear cell cultures up to 28-fold-more efficiently than the corresponding IgG and neutralized all of the primary isolates tested. The 2F5 and 2G12 antibodies of all isotypes were able to interact with active human serum to inhibit viral infection. Furthermore, we demonstrated that polymeric 2F5 and 2G12 antibodies but not the corresponding IgGs could interfere with HIV-1 entry across a mucosal epithelial layer in vitro. Although polymeric 2F5 antibodies had only limited potential in the standard neutralization assay, the results from the mucosal assay suggest that 2F5 and 2G12 antibodies may have a high potential to prevent natural HIV-1 transmission in vivo.

scholarly journals Coupled Integration of Human Immunodeficiency Virus Type 1 cDNA Ends by Purified Integrase In Vitro: Stimulation by the Viral Nucleocapsid Protein

1999 ◽  
Vol 73 (8) ◽  
pp. 6670-6679 ◽  
Author(s):  
Sandrine Carteau ◽  
Robert J. Gorelick ◽  
Frederic D. Bushman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
New Class ◽  
Immunodeficiency Virus ◽  
Viral Nucleocapsid ◽  
Hiv 1

ABSTRACT Integration of retroviral cDNA involves coupled joining of the two ends of the viral genome at precisely spaced positions in the host cell DNA. Correct coupled joining is essential for viral replication, as shown, for example, by the finding that viral mutants defective in coupled joining are defective in integration and replication. To date, reactions with purified human immunodeficiency virus type 1 (HIV-1) integrase protein in vitro have supported mainly uncoupled joining of single cDNA ends. We have analyzed an activity stimulating coupled joining present in HIV-1 virions, which led to the finding that the HIV-1 nucleocapsid (NC) protein can stimulate coupled joining more than 1,000-fold under some conditions. The requirements for stimulating coupled joining were investigated in assays with mutant NC proteins, revealing that mutations in the zinc finger domains can influence stimulation of integration. These findings (i) provide a means for assembling more authentic integrase complexes for mechanistic studies, (ii) reveal a new activity of NC protein in vitro, (iii) indicate a possible role for NC in vivo, and (iv) provide a possible method for identifying a new class of inhibitors that disrupt coupled joining.

scholarly journals In Vitro Anti-Human Immunodeficiency Virus Activities ofZ- and E-Methylenecyclopropane Nucleoside Analogues and Their Phosphoro-l-Alaninate Diesters

1999 ◽  
Vol 43 (6) ◽  
pp. 1487-1490 ◽  
Author(s):  
Hiroyuki Uchida ◽  
Eiichi N. Kodama ◽  
Kazuhisa Yoshimura ◽  
Yosuke Maeda ◽  
Pope Kosalaraksa ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Nucleoside Analogues ◽  
Infectious Clones ◽  
Immunodeficiency Virus ◽  
Further Development ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Methyl Phenyl

ABSTRACT Nucleoside analogues with a Z- or anE-methylenecyclopropane moiety were synthesized and examined for activity against human immunodeficiency virus type 1 (HIV-1) in vitro. The addition of a methyl phenyl phosphoro-l-alaninate moiety to modestly active analogues resulted in potentiation of their anti-HIV-1 activity. Two such compounds, designated QYL-685 (with 2,6-diaminopurine) and QYL-609 (with adenine), were most potent against HIV-1 in vitro, with 50% inhibitory concentrations of 0.034 and 0.0026 μM, respectively, in MT-2 cell-based assays. Both compounds were active against zidovudine-resistant, didanosine-resistant, and multi-dideoxynucleoside-resistant infectious clones in vitro. Further development of these analogues as potential therapies for HIV-1 infection is warranted.

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