Integrases

Transposons are mobile DNA elements (sizes 2.5-23 kbp) that move from one place to another in the chromosome or onto extrachromosomal genetic elements within the same cell. They are flanked by inverted repeats at then-ends and encode among other proteins a transposase that is needed for the transposition process. Resistance genes in the transposon are often parts of integrons. These are structures that cany an integrase responsible for the insertion of the resistance gene cassettes into the integron. 

Insulin Desensitization Insulin Receptor Insulin Resistance Insulin Secretagogues Insulin-like Growth Factor Integrase Integrin, a 4(31 Integrin, a 4(3 7 Integrin, a IIb(3 3... 

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... 

Consequently, S-1360, a triazole analogue of DKA, was the first integrase strand transfer inhibitor (INSTI) to enter clinical trials, but the development was stopped during phase Eli (Billich 2003). Subsequently, a novel series of potent INSTIs, which replaced the 1,3-diketo acid moiety by an isosteric 8-hydroxy-1,6-naphthyridine core, showed improved metabohc stabihty (Zhuang et al. 2003). The compound L-870,810 moved into clinical trials, where it provided proof of concept in antiretroviral therapy-experienced and antiretroviral therapy-naive... 

Al-Kobaisi MF, Rixon FJ, McDougaU I, Preston VG (1991) The herpes simplex vims UL33 gene product is required for the assembly of fiiU capsids. Virology 180 380-388 Anthony NJ (2004) HlV-1 integrase a target for new AIDS chemotherapeutics. Curr Top Med... 

Chee MS, Bankeir AT, Beck S, Bohni R, Brown CM, Cerny R, Horsnel T, Hutchinson CAI, Kouzarides T, Martignetti JA, Preddie E, Satchwell SP, Tomlinson P, Weston KM, Barrel BG (1990) Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169, Curr Top Microbiol Immunol 154 125-170 Chiu TK, Davies DR (2004) Structure and function of HIV-1 integrase. Curr Top Med Chem 4 965-977... 

Espeseth AS, Felock P, Wolfe A, Witmer M, Grobler J, Anthony N, Egbertson M, Melamed JY, Young S, Hamill T et al (2000) HlV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc Natl Acad Sci USA 97 11244-11249... 

Esposito D, Craigie R (1999) HIV integrase structure and function. Adv Virus Res 52 319-333 Evering TH, Markowitz M (2007) Raltegravir (MK-0518) an integrase inhibitor for the treatment of HlV-1. Drugs Today (Bare) 43 865-877... 

Kehlenbeck S, Betz U, Birkmann A, Fast B, Goller AH, Henninger K, Lowinger T, Marrero D, Paessens A, Paulsen D, Pevzner V, Schohe-Loop R, Tsujishita H, Welker R, Kreuter J, Riibsamen-Waigmann H, Dittmer F (2006) Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore. J Virol... 

Pommier Y, Johnson AA, Marchand C (2005) Integrase inhibitors to treat HIV/AIDS, Nat Rev Drug Discov 4 236-248... 

Satoh M, Motomura T, Matsuda T, Kondo K, Ando K, Matsuda K, Miyake S, Uehara H (2005) 4-Oxoquinohne compounds and utilization thereof as HIV integrase inhibitors, PCT Int, Appl, WO 2005113508... 

Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Watanabe Y, Ohata Y, Doi S, Sato M, Kano M, Ikeda S, Matsuoka M (2008) Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol 82 764-774... 

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... 

A general mechanism of resistance is reducing the affinity of the antiretroviral compound for its mutant target protein. Resistance mutations associated with reduced affinity are observed during treatment failure with a fusion inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTl), integrase inhibitor, and protease inhibitors as reviewed in Chaps. 3,4, 6, and 7 (Hazuda et al. 2007 Hsiou et al. 2001 King et al. 2002 Mink et al. 2005). 

RT inhibitors Protease inhibitors Integrase inhibitors Entry inhibitors Others... 

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