HIV This Week

Nair V, Chi G. HIV integrase inhibitors as therapeutic agents in AIDS. Rev Med Virol 2007 Jul-Aug; 17(4):277-95

HIV-1 integrase is a protein of Mr 32 000 encoded at the 3’-end of the pol gene. Integration of HIV DNA into the host cell chromosomal DNA apparently occurs by a carefully defined sequence of DNA tailoring (3’-processing (3’P)) and coupling (integration) reactions. Integration of HIV DNA into human DNA represents the biochemical completion of the invasion of the human cell (e.g., T-cell) by HIV. Unlike major successes seen in the development of clinically approved anti-HIV agents against HIV reverse transcriptase and HIV protease, there are no FDA-approved anti-HIV drugs in clinical use where the mechanism of action is inhibition of HIV integrase. This review summarises some key advances in the area of integrase inhibitors with the major focus being on new generation inhibitors. Special emphasis is placed on diketo acids with aromatic and heteroaromatic moieties, diketo acids with nucleobase scaffolds, bis-diketo acids, functionalised naphthyridines and other isosteres of diketo acids. Data pertaining to integrase inhibition and in vitro anti-HIV activity are discussed. Mention is made of drugs in clinical trials, both past (S-1360, L-870,810 and L-870,812 and present (GS-9137 and MK-0518). Other promising drugs, including those from the authors’ laboratory, are referred. Resistant mutants arising from key integrase inhibitors and cross-resistance are indicated.  

Editors’ note: Clinical trials are currently underway of 2 new classes of antiretroviral drugs that target the viral co-receptor CCR5 and the viral integrase enzyme. For the latter, preventing the integration of HIV into human DNA (integration allows HIV to take over the cell machinery) is a critical challenge — and doing so without important side effects is key. If they work, integrase inhibitors could be particularly beneficial for people who have developed HIV resistance to drugs that target HIV’s two other major enzymes: reverse transcriptase and protease

Molecular umbrella compounds may function as novel topical microbicides to prevent HIV and HSV (herpes simplex virus) infection. In a preliminary structure-activity investigation, one umbrella compound, designated Spm8CHAS, was identified which inhibited both HIV and HSV infection with no cellular toxicity. The objectives of the current studies were to define its spectrum of antiviral activity, characterize its mechanism of action, and explore the possibility of combining Spm8CHAS with HIV-specific reverse transcriptase inhibitors. Spm8CHAS inhibited infection by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture. Ectocervical tissue explants exposed to HIV-1BaL in the presence of Spm8CHAS were completely protected (IC50=13.6 microg/ml), and transfer of virus to target T-cells via migratory cells was abolished (IC50=3.8 microg/ml). Spm8CHAS inhibited HSV-2 infection of epithelial cells 10,000-fold if present throughout the infection. Notably, adding Spm8CHAS to cultures following HSV entry significantly reduced viral infection, indicating that the drug also acts post-entry. Subsequent studies indicate that Spm8CHAS blocks cell to cell spread of HSV. Confocal microscopy using a fluorescently labelled analogue of Spm8CHAS demonstrated that this conjugate crosses the plasma cell membrane and is transported to the nucleus. Combinations of Spm8CHAS with UC-781 or PMPA in vitro exhibited additive anti-HIV activity with preserved anti-HSV activity. The ability of Spm8CHAS to inhibit primary isolates of HIV, block HSV infection post-entry, and cross cell membranes supports the development of a combination microbicide containing Spm8CHAS with an HIV-specific reverse transcriptase inhibitor to prevent both HIV and HSV by multiple mechanisms.

Editors’ note: Molecular umbrella compounds can inhibit both HIV and HSV. In vitro testing of this one – Spm8CHAS – suggests that its ability to inhibit HIV infection (cross-clade), block HIV transfer to T-cells via migratory cells and block HSV spread from cell to cell, if combined with an HIV specific reverse transcriptase inhibitor, would create a potent combo that holds promise for the prevention not only of HIV acquisition but of HSV as well.