Virus Entry as a Target for Anti-HIV Intervention

Abstract

The replicative cycle of the human immunodeficiency virus (HIV) can be interrupted at several stages. Until recently only the viral reverse transcriptase and protease were the only enzymes targeted by antiretroviral agents. However, the first HIV entry inhibitor (T-20, Enfuvirtide, Fuseon) to be used in humans has been approved by the Food and Drug Administration (FDA). The HIV entry process is considered as an attractive target for chemotherapeutic intervention, as blocking HIV entry into its target cell leads to suppression of viral infectivity, replication and the cytotoxicity induced by virus-cell contacts. HIV-1 entry into target cells is a multistep process: virus attachment is initiated by the binding of trimeric envelope glycoprotein gp120 complexes on the virions to glycosylated T-cell surface receptor (CD4) and HIV GPCR coreceptors (CCR5 or CXCR4) leading to envelope glycoprotein gp41-dependent fusion-pore formation and membrane fusion. A number of compounds are being developed to specifically target each of these steps leading to virus entry and some compounds have reached early clinical development. Conversely, agents such as the CCR5 antagonist Tak-779 and the CXCR4 antagonist AMD3100 are not longer being thought as relevant anti-HIV agents but have given way to new analogues with improved properties. This review summarizes the current state of HIV entry inhibitors, their mechanisms of action and their therapeutic value against HIV infection and AIDS.

T-cell protection and enrichment through lentiviral CCR5 intrabody gene delivery

“…[7][8][9][10]50 Currently, there are a number of chemokine receptor antagonists under review. 40,41,[51][52][53] An alternative therapeutic method for disrupting HIV entry is the use of gene delivery to provide a genetic means to alter expression or block the function of chemokine receptors, for example, intrabodies, ribozymes, intrakines, zinc-fingers or RNAi. [13][14][15][16]54 Our approach to disrupting CCR5 expression on the cell surface relies on cellular expression of a humanized intrabody targeting CCR5.…”

Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5

“…Nevertheless, it would be reasonable to speculate that the involvement of additional amino acid residues in the binding of TAK-220 to huCCR5 should enhance the affinity of the drug to the binding pocket of the coreceptor molecule. In fact, inhibitory activity of TAK-220 on huCCR5-mediated HIV-1 infection appears to be higher than that of TAK-779 (26).…”

“…These include (i) small-molecule CCR5 antagonists (TAK-779 [3], UK-427857 [9], SCH-D [4], and AK602 [35]) or a CXCR4 antagonist (AMD070 [44]), (ii) chemokine analogues with modified amino-termini (11), (iii) the receptor mimic, soluble CD4 (2), (iv) peptide fusion inhibitors T20 (31) and T1249 (14), and (v) neutralizing antibodies that bind gp120 or gp41 (13). Smallmolecule CCR5 antagonists such as SCH-C (8,25), UK-427857 (43), SCH-D (43), and AK602 (38) have been shown to cause viral load reductions after administration to HIV-1-infected individuals in phase IIa clinical trials (26).…”

Cell-penetrating and cell-targeting peptides in drug delivery

“…Indeed, nowadays, peptide chemistry is easy and quite cheap for peptides up to 15 amino acids, and they can be synthesized with rather good yields. Although some longer peptides have also reached the drug market (the best known among them is probably the 36 amino acid-long T20 or Fuseon, used for antiviral treatment of HIV (for a review [128])), the synthesis of such large peptides is more complicated and requires more expensive production techniques. Peptide length could also be a concern when considering the structural aspects of the peptide-ligand interactions.…”