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Document Page 113 Follow-up studies were also reported for two previously identified classes of integrase inhibitors. Several nucleotides that were more effective inhibitors than the originally tested AZT nucleotides were identified [71]. For example, the L-enantiomers of 5-fluoro-2',3'-dideoxycytidine monophosphate and triphosphate inhibit 3' processing and strand transfer with IC 50 values of ~40 μM. A structure-function study on GT-containing oligonucleotides showed that both the number of quartets formed and the loop sequences between the quartets are important for activity, and that inhibitors of this type may function by interacting with the N-terminus of integrase [72]. A particularly important contribution was the demonstration that preintegration complexes isolated from HIV-infected lymphoid cells can be used in assays to screen for inhibition of integration [70]. Intriguingly, many compounds previously identified as in vitro inhibitors of 3' processing and strand transfer had no effect on integration carried out by either crude or partially purified preintegration complexes. Thus, such an assay may be a valuable method of screening out “false positives” identified using in vitro oligonucleotide assays, or corroborating the evidence that a particular compound is indeed active against integrase. Acknowledgments Our work described here was carried out in the laboratories of R. Craigie and D. R. Davies. We express our gratitude to our co-workers who, over the years, participated in the effort to determine the structure of HIV integrase. In particular, we acknowledge the contributions of F. D.Bushman, M. Carmichael, A. Engelman, S. Hosseini, T. Jenkins, K. Mizuuchi, I. Palmer, P. Rice, P. Sun, and P. Wingfield. We would also like to thank D. R. Davies and T. Jenkins for their comments on the manuscript and A. Mazumder for alerting us to the most recent work on integrase inhibitors and for his contributions to Section V.A. References 1. AIDS WEEKLY Plus. Key KK, ed. Atlanta, Charles Henderson Publisher, 1996: Feb. 5 & 12, p. 14. 2. Cara A, Guarnaccia F, Reitz, Jr. MS, Gallo RC, Lori F. Self-limiting, cell type-dependent replication of an integrase-defective human immunodeficiency virus type 1 in human primary macrophages but not T lymphocytes. Virol 1995, 208:242–248. 3. Dyda F, Hickman AB, Jenkins TM, Engelman A, Craigie R, Davies DR. Crystal structure of the catalytic domain of HIV-1 integrase: Similarity to other polynucleotidyl transferases. Science 1994; 266:1981–1986. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_113.html [4/5/2004 4:52:27 PM]
Document 4. Vink C, Plasterk RHA. The human immunodeficiency virus integrase protein. Trends Genet 1993; 9:433–437. Page 114 5. Katz RA, Skalka AM. The retroviral enzymes. Annu Rev Biochem 1994; 63:133–173. 6. Sherman PA, Fyfe JA. Human immunodeficiency virus integration protein expressed in Escherichia coli possesses selective DNA cleaving activity. Proc Natl Acad Sci USA 1990; 87:5119–5123. 7. Bushman FD, Craigie R. Activities of human immunodeficiency virus (HIV) integration protein in vitro: Specific cleavage and integration of HIV DNA. Proc Natl Acad Sci USA 1991; 88:1339–1343. 8. Engelman A, Mizuuchi K, Craigie R. HIV-1 DNA integration: Mechanism of viral DNA cleavage and DNA strand transfer. Cell 1991; 67:1211–1221. 9. Chow SA, Vincent KA, Ellison V, Brown PO. Reversal of integration and DNA slicing mediated by integrase of human immunodeficiency virus. Science 1992; 255:723–726. 10. Grandgenett DP, Vora AC, Schiff RD. A 32,000-dalton nucleic acid-binding protein from avian retravirus cores possesses DNA endonuclease activity. Virol 1978; 89:119–132. 11. Vincent KA, Ellison V, Chow SA, Brown PO. Characterization of human immunodeficiency virus type 1 integrase expressed in Escherichia coli and analysis of variants with amino-terminal mutations. J. Virol 1993; 67:425–437. 12. Hickman AB, Palmer I, Engelman A, Craigie R, Wingfield P. Biophysical and enzymatic properties of the catalytic domain of HIV-1 integrase. J Biol Chem 1994; 269:29279–29287. 13. Jones KS, Coleman J, Merkel GW, Laue TM, Skalka AM. Retroviral integrase functions as a multimer and can turn over catalytically. J Biol Chem 1992; 267:16037–16040. 14. Engelman A, Bushman FD, Craigie R. Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex. EMBO J 1993; 12:3269–3275. 15. Andrake MD, Skalka AM. Multimerization determinants reside in both the catalytic core and C terminus of avian sarcoma virus integrase. J Biol Chem 1995; 270:29299–29306. 16. Kalpana GV, Goff SP. Genetic analysis of homomeric interactions of human immunodeficiency virus type 1 integrase using the yeast two-hybrid system. Proc Natl Acad Sci USA 1993; 90:10593–10597. 17. Van Gent DC, Vink C, Oude Groeneger AAM, Plasterk RHA. Complementation between HIV integrase proteins mutated in different domains. EMBO J 1993; 12:3261–3267. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_114.html (1 of 2) [4/5/2004 4:52:29 PM]
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Document [Inhibitors] 2-((3,4-dihyd
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Document antagonistic activity, 416
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Document [Interleukin-1] homology w
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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