16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

BIOCHEMICAL AND ANTIVIRAL ACTIVITY OF MK-0518, A POTENT HIV INTEGRASE INHIBITOR

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThAa0302

Miller M.¹, Witmer M.¹, Stillmock K.¹, Felock P.¹, Ecto L.², Flynn J.², Schleif W.², Dornadula G.¹, Danovich R.¹, Hazuda D.^1
1 Merck Research Laboratories, Department of Antiviral Research, West Point, United States, ² Merck Research Laboratories, Vaccines and Biologics Research, West Point, United States

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 α, β, and γ.

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.

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2006-08-13
ThAa0302

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