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Abstract
Biochemical and antiviral activity of MK-0518, a potent HIV integrase inhibitor
M. Miller1, M. Witmer1, K. Stillmock1, P. Felock1, L. Ecto2, J. Flynn2, W. Schleif2, G. Dornadula1, R. Danovich1, D. Hazuda1
Background: Many drugs approved for treatment of HIV infection are plagued by problems of cross-resistance. One way to address this problem is to develop antiviral compounds directed at new targets such as HIV integrase. This presentation details the biochemical and antiviral activities of MK-0518, an HIV integrase inhibitor in clinical development.
Results: MK-0518 inhibited the strand transfer activity of purified HIV-1 integrase in vitro with an apparent IC50 of 2-7nM. MK-0518 shows >1000-fold selectivity for HIV-1 integrase as compared with other phosphoryltransferases tested, including the polymerase and RNase H activities of HIV-1 reverse transcriptase and the human polymerases a, b, and g.
MK-0518 blocked HIV replication in a multiple-cycle replication assay with IC95s of 19 +/- 14 nM and 33 +/- 23 nM when tested in the presence of 10% fetal bovine serum or 50% normal human serum, respectively. Antiviral mechanism-of-action studies indicated that MK-0518’s antiviral activity is attributable to blocking integrase during infection: quantitative PCR assays showed that MK-0518 did not affect synthesis of HIV cDNA but prevented integration into cellular DNA (Alu-LTR PCR assay) and enhanced the formation of dead-end 2-LTR circular DNA forms.
When tested in combination with other antiretroviral agents, MK-0518 was additive/synergistic with all licensed anti-HIV drugs (except tipranivir, not tested).
MK-0518 was similarly active against a broad panel of HIV isolates, including primary isolates from a variety of subtypes, isolates resistant to PIs, NRTIs, and NNRTIs, and even against SIV.
Conclusions: MK-0518 is a potent HIV integrase inhibitor that displays broad antiviral activity against HIV isolates, including isolates resistant to other classes of HIV drugs. The virological profile of MK-0518 support its use in combination with all other classes of antiretroviral agent.
AIDS 2006 - XVI International AIDS Conference
Abstract no.
THAA0302
Suggested Citation
"M.Miller, et al.
Biochemical and antiviral activity of MK-0518, a potent HIV integrase inhibitor.
Oral abstract session:
AIDS 2006 - XVI International AIDS Conference:
Abstract no.
THAA0302"
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