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cubation of phosphotyrosine with integrase has been shown to inhibit interaction with the MA protein
[65]. Therefore, phosphotyrosine analogs could be a unique approach to antiviral development.
D. Concluding Statement
Page 112
It is known from drug design studies with HIV reverse transcriptase and protease that the virus is able to
escape from the pressures of inhibitors by mutation of the drug targets [66]. Although integrase is, a
priori, a reasonable target for drug-design efforts, it must be anticipated that integrase will also be able
to rapidly mutate and thereby avoid inhibition.
By analogy with recent approaches to reverse transcriptase inhibitors, it may be possible to design a set
of integrase inhibitors that act at slightly different binding sites and from which the virus cannot
simultaneously escape. That is, the combination of mutations required to avoid inhibition may be severe
enough to prevent integrase from carrying out its required chemistry. (In the absence of direct structural
information on the sites of inhibitor binding to integrase, the generation of escape mutants in vitro and
their subsequent sequencing may be an indirect way to identify inhibitor binding sites.) It will also be
important to determine if the virus will be able to simultaneously mutate reverse transcriptase, integrase,
and the protease in response to a combination of inhibitors targeted against all three pol gene products.
The answers to these questions will require the development of suitable inhibitors and the beginning of
in vitro testing. To this end—while large-scale screening and the development of combinatorial
chemistry methods should continue—the structure of the catalytic core domain of HIV-1 integrase is a
starting point for the rational design of integrase inhibitors. There is much more structural information
that must be obtained for the full-length protein and its complexes with metals, inhibitors, and
substrates. We and others are aggressively pursuing results on these fronts.
E. Recent Developments
Several studies published since March 1996 have expanded the list of in vitro integrase inhibitors
effective at IC 50 values below 100 μM. These include two dicaffeoylquinic acids obtained from
medicinal plants and a synthetic analog, L-chicoric acid [68], the HIV protease inhibitors NSC 117027
and NSC 158393 [69], certain anthraquinone derivatives [70], coumermycin, and pyridoxal phosphate
[71]. In addition to exhibiting in vitro inhibition, the dicaffeoylquinic acids effectively inhibited HIV-1
replication in T-lymphoblastoid cell lines [68].
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