ancriviroc and HIV-Infections

Human immunodeficiency virus (HIV) is a retrovirus that is the causative agent of acquired immunodeficiency syndrome (AIDS). Current HIV therapy is based on targeting two critical enzymes in the viral replication machinery: reverse transcriptase and a virally encoded protease. Although mortality rates due to HIV infection have been dramatically reduced, AIDS remains a major health problem throughout the world. The emergence of HIV variants that are resistant to current therapies and potential toxicity associated with their chronic use has highlighted the need for new approaches to HIV inhibition. Identification of the mechanisms underlying viral entry into the host cell has provided a number of novel therapeutic targets and the first of these HIV fusion inhibitors (enfuvirtide [pentafuside, T-20, Fuzeon; Roche Laboratories and Trimeris]) has recently been approved in the US and Europe. This review will focus on recent progress in the development of therapeutics that target the HIV entry process.

Topics: Amino Acid Motifs; Animals; Anti-HIV Agents; CCR5 Receptor Antagonists; CD4 Antigens; Clinical Trials as Topic; Cyclic N-Oxides; Dogs; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Haplorhini; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Membrane Fusion; Membrane Glycoproteins; Organic Chemicals; Oximes; Peptide Fragments; Piperazines; Piperidines; Protein Binding; Pyridines; Pyrimidines; Rabbits; Receptors, CCR5; Receptors, CXCR4; Reverse Transcriptase Inhibitors; Spiro Compounds

Schering-Plough is developing Sch-351125 (Sch-C), the lead in a series of CCR5 inhibitors, for the potential treatment of HIV infection. By March 2001, it had entered phase I studies in the US, however, by April 2001, these had been suspended based in part on observed QTc prolongation at the highest dose. By December 2001, a new phase I trial had been initiated in France. The company has continued to investigate a number of second-generation CCR5 receptor antagonists, including Sch-350634, for the potential treatment of HIV infection. Although it was reported at two separate meetings in early 2001 that Sch-350634 was in phase I/II trials, in April 2001, Schering-Plough confirmed that the compound was not in clinical development at that time and that a preclinical toxicology program was scheduled for late 2001. In December 2001, Morgan Stanley predicted a 2004 launch for a compound arising from the CCR5 inhibitor program, with sales of US$100 million in 2004, US$200 million in 2005, rising to US$300 million in 2006.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cyclic N-Oxides; HIV Infections; Humans; Oximes; Piperazines; Piperidines; Pyridines; Structure-Activity Relationship

HIV-1 coreceptors are attractive targets for novel antivirals. Here, inhibition of entry by two classes of CCR5 antagonists was investigated. We confirmed previous findings that HIV-1 isolates vary greatly in their sensitivity to small molecule inhibitors of CCR5-mediated entry, SCH-C and TAK-779. In contrast, an anti-CCR5 monoclonal antibody (PA14) similarly inhibited entry of diverse viral isolates. Sensitivity to small molecules was V3 loop-dependent and inversely proportional to the level of gp120 binding to CCR5. Moreover, combinations of the MAb and small molecules were highly synergistic in blocking HIV-1 entry, suggesting different mechanisms of action. This was confirmed by time course of inhibition experiments wherein the PA14 MAb and small molecules were shown to inhibit temporally distinct stages of CCR5 usage. We propose that small molecules inhibit V3 binding to the second extracellular loop of CCR5, whereas PA14 preferentially inhibits subsequent events such as CCR5 recruitment into the fusion complex or conformational changes in the gp120-CCR5 complex that trigger fusion. Importantly, our findings suggest that combinations of CCR5 inhibitors with different mechanisms of action will be central to controlling HIV-1 infection and slowing the emergence of resistant strains.

Topics: Amides; Anti-HIV Agents; Antibodies, Monoclonal; CCR5 Receptor Antagonists; Cyclic N-Oxides; Drug Synergism; HeLa Cells; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; In Vitro Techniques; Oximes; Peptide Fragments; Piperidines; Pyridines; Quaternary Ammonium Compounds; Receptors, CCR5; Recombinant Proteins

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclic N-Oxides; Drugs, Investigational; Enfuvirtide; Furans; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV Integrase Inhibitors; Humans; Nitriles; Oximes; Peptide Fragments; Piperazines; Piperidines; Pyridazines; Pyridines; Pyrimidines; Reverse Transcriptase Inhibitors; Triazoles

SCH-C (SCH 351125) is a small-molecule antagonist of the human immunodeficiency virus type 1(HIV-1) coreceptor CCR5. It has in vitro activity against R5 viruses with 50% inhibitory concentrations ranging from 1.0 to 30.9 nM. We have studied anti-HIV-1 interactions of SCH-C with other antiretroviral agents in vitro. Synergistic interactions were seen with nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine), nonnucleoside reverse transcriptase inhibitors (efavirenz), and protease inhibitors (indinavir) at all inhibitory concentrations evaluated. We have also studied antiviral interactions between the HIV-1 fusion inhibitor T-20 and SCH-C against a panel of R5 HIV-1 isolates. We found synergistic interactions against all the viruses tested, some of which harbored resistance mutations to reverse transcriptase and protease inhibitors. Anti-HIV-1 synergy was also observed between SCH-C and another R5 virus inhibitor, aminooxypentane-RANTES. These findings suggest that SCH-C may be a useful anti-HIV drug in combination regimens and that a combination of chemokine coreceptor/fusion inhibitors may be useful in the treatment of multidrug-resistant viruses.

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Cyclic N-Oxides; Drug Interactions; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Oximes; Piperidines; Pyridines; Reverse Transcriptase Inhibitors

Topics: AIDS Vaccines; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Antigens; Clinical Trials as Topic; Cyclic N-Oxides; Enfuvirtide; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; Humans; Membrane Fusion; Oximes; Patient Compliance; Peptide Fragments; Piperidines; Pyridines; Receptors, HIV

Topics: Adenine; Anti-HIV Agents; Clinical Trials as Topic; Cyclic N-Oxides; HIV Infections; Humans; Nitriles; Organophosphonates; Organophosphorus Compounds; Oximes; Piperidines; Pyridazines; Pyridines; Pyrimidines; Tenofovir

Topics: AIDS Vaccines; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cyclic N-Oxides; HIV; HIV Infections; Humans; Oximes; Piperidines; Pyridines; Retroviridae; T-Lymphocytes, Cytotoxic; Treatment Failure; Washington