Integrase, viral

HIV integrase consists of three distinct domains. The N-terminal domain contains a HHCC motif that coordinates a zinc atom that is required for viral cDNA integration. Three highly conserved amino acids (D,D-35-E) are embedded in the core domain, which form the acidic catalytic triad coordinating one or possibly two divalent metals (Mn + or Mg +). The C-terminal domain (residues 213-288) is responsible for unspecific DNA binding and adopts an overall SH3 fold (Chiu and Davies 2004). The enzyme functions as a multimer and to this end all three domains can form homodimers. 

The integration of newly synthesized viral DNA into the host chromosome is a multi-step process (Anthony 2004 Van Made and Debyser 2005) that relies on the integrity of the last 10-20 base pairs at both ends of the viral cDNA besides a fully functional integrase (see Fig. 1). Initially, integrase recogiuzes the long-terminal repeat (LTR) of the retro-transcribed viral DNA and performs endonucleolytic... 

Underwood M, Harvey R, Stanat S, Hemphill M, Miller T, Drach J, Townsend L, Biron K (1998) Inhibition of human cytomegalovirus DNA maturation by a benzimidazole ribonucleoside is mediated through the UL89 gene product. J Virol 72 717-725 Van Maele B, Debyser Z (2005) HlV-1 integration an interplay between HIV-1 integrase, cellular, and viral proteins. AIDS Rev 7 26 3... 

Okui N, Kobayashi N, Kitamura Y (1998) Production of uninfectious human immunodeficiency virus type 1 containing viral protein R fused to a single-chain antibody against viral integrase. J Virol 72 6960-6964... 

The enzyme reverse transcriptase, as well as some other enzymes used in virus replication the gene that codes these enzymes is the pol gene. The other viral enzymes specified by the pol gene are protease and integrase. Protease is involved in muturation of viral proteins as the virus buds out from the cell, and integrase is responsible for integration of the viral DNA into the cell s chromosomal DNA. 

The pol gene, responsible for formation of viral enzymes protease, reverse transcriptase, and endonuclease (integrase). 

Drugs known as integrase inhibitors and maturation inhibitors are also in development. Integrase inhibitors are designed to interfere with the integration of the viral genome while the maturation inhibitors specifically block the conversion of the HlV-1 capsid precursor, CA-SPl (p25) to mature capsid protein (p24). This blocking will result in defective core condensation and the release of noninfectious virus particles. 

Replication of the human immunodeficiency virus (mV), the causative agent of AIDS, is susceptible to targeted interventions, because several virus-specific metabolic steps occur in infected cells (A). Viral RNA must first be transcribed into DNA, a step catalyzed by viral reverse transcriptase." Double-stranded DNA is incorporated into the host genome with the help of viral inte-grase. Under control by viral DNA, viral replication can then be initiated, with synthesis of viral RNA and proteins (including enzymes such as reverse transcriptase and integrase, and structural proteins such as the matrix protein lining the inside of the viral envelope). 

Liao, C.Z., Karki, R.G., Marchand, C., Pommier, Y., Nicklaus, M.C. Virtual screening application of a model of full-length HIV-1 integrase complexed with viral DNA. Bioorg. Med. Chem. Lett. 2007, 17, 5361-5. 

In addition to fusion inhibitors, novel viral enzymes (e.g., integrase) are also being studied integrase inhibitors may constimte a new direction in antiviral therapy. Viral serine proteases have likewise been identified as attractive antiviral targets. Based upon crystallographic structural data, novel peptidomimetic inhibitors are being developed. 

It has been demonstrated that the chemical steps that comprise DNA integration are carried out by the viral protein, integrase (IN). Integrase is encoded by the 3 end of the viral pol gene, which also codes for two other viral enzymes, the protease and reverse transcriptase. These three enzymes are initially synthesized as part of a larger polyprotein that is subsequently cleaved by the protease to the individual proteins. 

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