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Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore

Kehlenbeck, S ; Betz, U ; Birkmann, A ; Fast, B ; Göller, A H ; Henninger, K ; Lowinger, T ; Marrero, D ; Paessens, A ; Paulsen, D ; Pevzner, V ; Schohe-Loop, R ; Tsujishita, H ; Welker, R ; Kreuter, J ; Rübsamen-Waigmann, H ; Dittmer, F

Journal of virology, July 2006, Vol.80(14), pp.6883-94 [Tạp chí có phản biện]

ISSN: 0022-538X ; PMID: 16809294 Version:1

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  • Nhan đề:
    Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore
  • Tác giả: Kehlenbeck, S ; Betz, U ; Birkmann, A ; Fast, B ; Göller, A H ; Henninger, K ; Lowinger, T ; Marrero, D ; Paessens, A ; Paulsen, D ; Pevzner, V ; Schohe-Loop, R ; Tsujishita, H ; Welker, R ; Kreuter, J ; Rübsamen-Waigmann, H ; Dittmer, F
  • Chủ đề: HIV Infections -- Metabolism ; HIV Integrase -- Metabolism ; HIV Integrase Inhibitors -- Pharmacology ; HIV-1 -- Metabolism ; Virus Integration -- Drug Effects
  • Là 1 phần của: Journal of virology, July 2006, Vol.80(14), pp.6883-94
  • Mô tả: We have identified dihydroxythiophenes (DHT) as a novel series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors with broad antiviral activities against different HIV isolates in vitro. DHT were discovered in a biochemical integrase high-throughput screen searching for inhibitors of the strand transfer reaction of HIV-1 integrase. DHT are selective inhibitors of integrase that do not interfere with virus entry, as shown by the inhibition of a vesicular stomatitis virus G-pseudotyped retroviral system. Moreover, in quantitative real-time PCR experiments, no effect on the synthesis of viral cDNA could be detected but rather an increase in the accumulation of 2-long-terminal-repeat cycles was detected. This suggests that the integration of viral cDNA is blocked. Molecular modeling and the structure activity relationship of DHT demonstrate that our compound fits into a two-metal-binding motif that has been suggested as the essential pharmacophore for diketo acid (DKA)-like strand transfer inhibitors (Grobler et al., Proc. Natl. Acad. Sci. USA 99:6661-6666, 2002.). This notion is supported by the profiling of DHT on retroviral vectors carrying published resistance mutations for DKA-like inhibitors where DHT showed partial cross-resistance. This suggests that DHT bind to a common site in the catalytic center of integrase, albeit with an altered binding mode. Taken together, our findings indicate that DHT are novel selective strand transfer inhibitors of integrase with a pharmacophore homologous to DKA-like inhibitors.
  • Ngôn ngữ: English
  • Số nhận dạng: ISSN: 0022-538X ; PMID: 16809294 Version:1

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