HIV integrase: a target for drug discovery

Abstract

Current antiviral strategies against HIV rely on structure–function analysis of HIV reverse transcriptase (RT) and protease (PR). The third viral pol gene product, HIV integrase (IN), is also a good target for drug discovery, since IN is essential for retroviral replication and, moreover, it has no obvious functional analogue in the host. IN forms a ternary complex with metal ions and DNA and has a mechanism of catalysis common with other polynucleotidyl transferases. Although there is no structural information for full‐length IN available, structures of all three functional IN domains have been determined by X‐ray crystallography and NMR spectroscopy. The N‐terminal domain has a novel zinc‐binding fold, the catalytic domain shares a common structural motif with other polynucleotidyl transferases, and the C‐terminal DNA‐binding domain has a Src‐homology‐3‐like fold. This structural information provides the basis for drug development. In turn, increasing numbers of IN inhibitors identified so far may serve structure–function analysis of IN. The final goal is the development of new classes of anti‐HIV drugs, which can be added to the repertoire of anti‐RT and anti‐PR drugs.

Mapping the Epitope of an Inhibitory Monoclonal Antibody to the C-terminal DNA-binding Domain of HIV-1 Integrase

“…The protein distribution was analyzed by SDS-PAGE electrophoresis, followed by quantitation with Quantity One computer software (Bio-Rad). integration (33,34). The isolated C-terminal domain exists as a specific homodimer at concentrations of ϳ1 mM (16 -18).…”

Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: A model for viral DNA binding

“…Although the C-terminal interactions involving adjacent HIV-1 IN 52-288 dimers determine the crystal packing, they and the dimer interface in the isolated C-terminal structure may represent favorable interactions that facilitate the higher-order complex required for properly spaced, concerted integration into the host DNA. Mutagenesis of residues within the C-terminal domains suggests that higher-order oligomerization of HIV-1 IN in solution is facilitated by the C-terminal domains (33,34).…”

Protein trans-Acting Factors Involved in Ribosome Biogenesis in Saccharomyces cerevisiae

“…However, there is no evidence for stable physical interactions between these putative RNA helicases and snoRNAs (81,191) and they therefore probably associate only transiently. Recombinant Rrp3p (cited in reference 133) and Rok1p display ATPase activity in vitro (136,143), and recombinant Dbp4p binds nonspecifically to RNA and has an intrinsic ATPase activity that is not stimulated by the addition of U14, 18S rRNA, or total RNA (81).…”