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(for example, compound VIII, aka AG1717). In cell-based screening assays, AG1717 demonstrated
some antiviral activity [50].
Page 107
Another study that demonstrated a role for ortho hydroxyl groups in in vitro integrase inhibition
identified β-conidendrol (IX) via random screening as an inhibitor with an IC 50 value of less than 1 μM
[51]. Although β-conidendrol did not inhibit several other nucleic-acid processing enzymes, indicating
some specificity for integrase, it was not active in cell-based antiviral assays at concentrations as high as
100 μM.
Other Classes of Integrase Inhibitors
Several compounds and their derivatives that do not contain adjacent hydroxy groups on a phenyl ring
have recently been identified as HIV integrase inhibitors. These include suramin (X), curcumin (XI),
phenanthroline-Cu + complexes (XII), and 3'-azido-3'-deoxythymidylate (AZT) monophosphate (XIII).
Suramin (X) is a known inhibitor of DNA and RNA polymerases, retroviral reverse transcriptases, and
topoisomerase II. It has also been shown to prevent the infection of T lymphocytes by HIV in vitro [52].
Its six sulfonic acid groups confer a strong negative charge, and it was reasoned that there might be an
inhibitory electrostatic interaction with the positive residues of the HIV C-terminus domain. Suramin
was shown to be an effective inhibitor of 3' processing and strand transfer, with IC 50 values of 0.25 μM
and 0.11 μM, respectively [53]. It was not demonstrated, however, that the mechanism of inhibition does
involve binding to the C-terminus of integrase, although this could be readily addressed using Cterminal
truncated mutants active for disintegration.
Curcumin (XI), the coloring dye in the spice turmeric, is structurally related to CAPE (V). It has also
been shown to inhibit HIV replication by inhibiting p 24 antigen production and tat-mediated transcription
[54]. As shown in Table 1, it also has moderate integrase inhibitory properties [55]. Although its two-
OH groups are neither adjacent to each other nor on the same phenyl ring, its conformations can be
modeled to bring the hydroxy groups into close proximity by stacking the two phenyl rings on each
other.
Several tetrahedral cuprous phenanthroline complexes, known inhibitors of transcription, were tested
against integrase and shown to be reasonably effective inhibitors [56]: IC 50 values in the range of 1–10
μM were determined (for example, the neocuproine-Cu + complex, XII). Analyses of the mode of
inhibition demonstrated that these compounds act noncompetitively, and that inhibition does not
correlate with inhibition of DNA binding. Thus, it has been proposed that these metal chelates may act
at a site distant from the active site, or perhaps in the context of an enzyme-DNA complex.
3'-Azido-3'-deoxythymidine, or AZT, is a nucleoside analog approved for use to treat AIDS. Its
metabolites, the mono-, di- and triphosphate forms, accu-
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