In an effort to further extend the number of targets for development of anti-retroviral agents, we are studying HIV-1 integrase inhibitors using in vitro assays using recombinant enzyme and short oligonucleotides corresponding to the proviral ends (LTR's). Integrase is a rationale target for inhibitor development because it is essential for viral replication. It is also encoded by HIV and does not have a cellular equivalent. Our laboratory has pioneered this research field and reported various families of inhibitors. We have continued our studies on polyhydroxylated aromatics with Dr. Burke. Because one of them, caffeoylquinic acid is antiviral, we performed structure-activity studies on chicoric acid analogs. We found that blocking the catechol functionality through conversion to tetraacetate esters results in almost no loss of potency, contingent of the presence of at least one carboxyl group on the central linker. Taken as a whole, our work has resulted in the identification of new integrase inhibitors, which may be regarded as bis-caffeoyl derivatives with antiviral activity. We also discovered a novel family of HIV integrase inhibitors, the thiazolothiazepine that are non-catechol inhibitors. Remarkably, these thiolothiazepine derivatives are active in magnesium (considered to be the physiological divalent cation) as well as in maganese-based assays (which are more robust in vitro). They are antiviral without inhibiting other retroviral targets besides integrase. Further work will be needed to determine whether integrase is the only in vivo target of this new class of drugs. We are also studying novel types of inhibitors that can prevent integration by binding to the proviral DNA ends as well as small peptide and nucleotide inhibitors.
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