INTEGRASE INHIBITION — Study Summaries

The following summaries highlight the key points of relevant articles. To view the full article, click on the publisher link provided.

Discovery of natural product inhibitors of HIV-1 integrase at Merck by Singh SB, et al. (Drugs of the Future. 2005;30[3]:277–299)—In this paper, the investigators focus on the methods and results of their extensive screening of natural products to discover and identify potential drug candidates that would target HIV-1 integrase. They conclude that “The early discovery of a number of these compounds (eg, equisetin, integric acid, integramycin and integracide A) led to further mechanistic understanding of HIV-1 integrase and the refinement of in vitro and cell-based assays, allowing the discovery of lead synthetic diketo acid inhibitors, which upon further optimization resulted in several clinical candidates (L-870810, etc.)."

Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaque by Hazuda DJ, et al. (Science. 2004;305:528–532) — The investigators in this study evaluated the efficacy of the HIV-1 and SIV integrase inhibitor L-870812 in rhesus macaques infected with the simian-human immunodeficiency virus. Their findings demonstrate the in vivo activity of integrase inhibitors and “suggest that cellular immunity facilitates chemotherapeutic efficacy in retroviral infections.”

Diketo acid inhibitor mechanism and HIV-1 integrase: implications for metal binding in the active site of phosphotransferase enzymes by Grobler JA, et al. (Proceedings of the National Academy of Sciences. 2002;99[10]:6661–6666) — In this paper, the researchers use functional assays and binding assays to evaluate a series of structurally related analogs in order to characterize the molecular basis of the inhibition of the strand transfer reaction of integrase (IN) in vitro and in infected cells. They conclude that their findings “have implications for modeling active site inhibitors of IN, designing and evaluating analogs with improved efficacy, and identifying inhibitors of other metal-dependent phosphotransferases.”

HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase by Espeseth AS, et al. (Proceedings of the National Academy of Sciences. 2000;97[21]:11244–11249) — The researchers in this study used a novel scintillation proximity assay to study the interactions of a diketo acid with integrase and to determine the mechanism of action. The researchers conclude that their findings “elucidate the basis for diketo acid inhibition of strand transfer and have implications for integrase-directed HIV-1 drug discovery efforts.”

A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase by Hazuda DJ, et al. (Proceedings of the National Academy of Sciences. 2004;101[31]:11233–11238)—In this paper, the investigators describe the identification and characterization of the HIV-1 integrase inhibitor L-870,810. Their findings “provide a structural basis and rationale for developing integrase inhibitors with the potential for unique and non-overlapping resistance profiles.”

Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells by Hazuda DJ, et al. (Science. 2000;287:646–650) — This report focuses on diketo acid inhibitors that have antiviral activity as a result of their action on integration. In conclusion, the researchers state, “We have noted that HIV-1 LTR sequences stimulate high-affinity binding of L-731,988 and related compounds to integrase, suggesting that integrase may adopt a distinct conformation subsequent to assembly. Together with the results presented, these observations provide biochemical and physical evidence dissociating the two catalytic functions of integrase and suggest that the diketo acids may be useful tools to probe the enzymatically active structure of integrase and to investigate the complexities of this reaction.”


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