5-(1-1-dioxido-1-2-thiazinan-2-yl)-n-(4-fluorobenzyl)-8-hydroxy-1-6-naphthyridine-7-carboxamide and Acquired-Immunodeficiency-Syndrome

HIV-1 integrase (IN) is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA. The unique properties of IN makes it an ideal target for drug design. First, there appears to have no functional equivalent in human cells and the reactions catalyzed by IN are unique. Second, IN is absolutely required for viral replication and mutations in a number of key residues block the viral replication. Third, IN has been validated as a legitimate target and the results from the molecules like S-1,360, JKT-303 which are under phase II/III clinical trials suggest synergistic effect with reverse transcriptase (RT) and protease (PR) inhibitors. During the past 10 years a plethora of inhibitors have been identified and some were shown to be selective against IN and block viral replication. The classes under which inhibitors of integrase can be classified are catechol-containing hydroxylated aromatics, diketoacid-containing aromatics, quninolines and others (non-catechol containing). In the present article we review all the recent small molecules reported to inhibit recombinant HIV-1 IN under these heads. It seems likely that the efficient use of HIV IN as target for rational design can give potent anti-HIV agents, which can be used alone or in combination regimens with other classes of anti-HIV drugs.

Topics: Acquired Immunodeficiency Syndrome; Cells, Cultured; HIV Integrase Inhibitors; Humans; Virus Replication