fp-21399 and HIV-Infections

FP-21399 is a bis(disulfonaphthalene) derivative that prevents human immunodeficiency virus (HIV) infection of uninfected cells by blocking entry of the virus. FP-21399 shows an affinity for lymph nodes. In this phase I study, FP-21399 was administered intravenously over 1 h as a single dose (0.9, 1.7, 2.8, and 4.2 mg/kg) or as a once-weekly infusion (1, 2, and 3 mg/kg) for 4 consecutive weeks to 34 HIV-1 infected patients with CD4(+) cell counts of 50-400 cells/microL. Concomitant antiretroviral therapy was permitted but not required. The most frequent adverse events involved the transient, dose-dependent appearance of drug- or metabolite-related color in the urine and skin. Plasma drug levels were linear with dose. The drug was cleared, with an elimination half-life of 4 h and a terminal half-life of 1.5-2 days; the terminal half-life represented redistribution and clearance from tissues. FP-21399 administered weekly for 4 weeks was well tolerated. Further studies are necessary to define the role of this fusion inhibitor in the treatment of HIV infection.

Topics: Adult; Anti-HIV Agents; Cell Fusion; Chlorobenzenes; Female; HIV Infections; Humans; Male; Middle Aged; Naphthalenes

The bis-azo compound FP-21399 inhibits HIV-1 infection. We now show that FP-21399 acts on the HIV-1 envelope glycoprotein to prevent viral replication. This compound targets the entry step of the HIV-1 replication cycle as demonstrated by time-of-addition and single cycle viral entry assays. The entry of SIVmac239, which uses the same coreceptors (CD4/CCR5) as HIV-1, was not inhibited by FP-21399, indicating that the antiviral effect of FP-21399 is specific for the HIV-1 envelope glycoprotein and is not dependent upon the cellular receptors CD4 and CCR5. FP-21399 inhibits neither the activity of HIV-1 reverse transcriptase nor the expression of HIV-1 early mRNA. Finally, this compound inhibits gp120 shedding of the T-tropic virus. Our results suggest that the anti-HIV activity of FP-21399 is due to its interaction with HIV-1 gp120/41 complex during viral entry.

Topics: Animals; Anti-HIV Agents; Base Sequence; Chlorobenzenes; DNA Primers; Gene Expression; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV-1; Humans; In Vitro Techniques; Leukocytes, Mononuclear; Membrane Fusion; Naphthalenes; Receptors, CCR5; Receptors, CXCR4; RNA, Messenger; RNA, Viral; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Virus Replication

Reports at the 5th Conference on Retroviruses and Opportunistic Infections addressed new anti-HIV agents in primary phases of development that offer treatment alternatives to people with little or no treatment history and individuals with few treatment choices. FTC, a new nucleoside analog produced by Triangle Pharmaceuticals, is an alternative to 3TC. F-ddA (lodenosine), a nucleoside analog licensed by US Bioscience, is structurally similar to ddI and is reported to have good bioavailability, once-a-day dosing, and no bone marrow suppression. F-ddA has also shown in vitro activity against multidrug-resistant strains of HIV. Adult and pediatric studies are currently being conducted by the National Cancer Institute (NCI) and US Bioscience. Oral versus IV PMPA shows promising results as a possible alternative for 3TC- and AZT-experienced patients. Further testing is being done by Gilead Sciences and HIV Network for Prevention Trials (HIVNET). Abbott Laboratories is developing a second-generation protease inhibitor, ABT-378, which has a ten-fold greater antiviral activity in vitro than the original, ritonavir. It is administered with ritonavir to increase ABT-378 levels in the blood, but has no food requirements, and less severe side effects. Two trials are being conducted: one for patients who are treatment-naive and the second for patients who are failing other protease inhibitors. Immune-based therapies, such as Leukine (GM-CSF), are used to handle neutropenia and offset bone marrow toxicities from drugs. Concerns that GM-CSF may increase viral replication may be balanced by using highly active antiretroviral therapy. FP-21399, developed by Lexigen Pharmaceuticals, is being tested as an HIV fusion inhibitor.

Topics: Adenine; Animals; Anti-HIV Agents; Biological Availability; Chlorobenzenes; Clinical Trials as Topic; Codon; Dideoxyadenosine; Drug Resistance, Microbial; Drugs, Investigational; Granulocyte-Macrophage Colony-Stimulating Factor; HIV Infections; HIV Protease Inhibitors; Humans; Naphthalenes; Organophosphonates; Pyrimidinones; Receptors, CCR5; Receptors, CXCR4; Reverse Transcriptase Inhibitors; Tenofovir

The identification of fusin and other chemokine receptors as coreceptors for HIV-1 has renewed the interest in agents that may prevent viral entry. Polyanionic compounds such as dextran sulfate, curdian sulfate, and suramin act on the V3 loop of the viral envelope and may prevent its interaction with fusin. These agents show activity against a wide range of HIV-1 strains, but have undesirable circulating half-life, bioavailability, and toxicity. We have developed a small molecule inhibitor of HIV-1 that has several advantages over these other agents. FP-21399 is a novel compound of the bis(disulfonaphthalene) dimethoxybenzene class that blocks entry of HIV into CD4+ cells and blocks fusion of infected and noninfected CD4+ cells. This compound only weakly inhibits binding of CD4 and gp120, at concentrations much greater than are required to block viral entry. Furthermore, FP-21399 can block the interaction between gp120 and antibodies directed against the V3 loop, but does not block binding of antibodies directed against the V4 loop. Animal studies demonstrate that FP-21399 is concentrated in lymph nodes, making it a promising compound for anti-HIV therapy. In SCID mice reconstituted with human immune cells, maintenance of HIV-1 infection was blocked by a 5-day treatment with low doses of FP-21399, suggesting that lymph node accumulation may contribute to antiviral activity. Finally, attempts to generate drug-resistant virus in cell culture resulted in only weakly resistant variants with IC90 values that are much lower than concentrations of FP-21399 found in lymph nodes.

Topics: Animals; Anti-HIV Agents; Biotechnology; CD4-Positive T-Lymphocytes; Cell Line; Chlorobenzenes; Dogs; Drug Resistance, Microbial; Gene Products, env; Genetic Variation; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Lymph Nodes; Male; Membrane Fusion; Mice; Mice, SCID; Naphthalenes; Peptide Fragments; Rats; Rats, Sprague-Dawley