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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.
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