[26] BISPHOSPHONATE INHIBITORS OF NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR EXCISION

13th International HIV Drug Resistance Workshop

8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain

BISPHOSPHONATE INHIBITORS OF NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR EXCISION

Antiviral Therapy 2004; 9:S32

MA Parniak¹, S McBurney¹, E Oldfield² and JW Mellors¹
¹Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pa.; and ²Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, Ill., USA

While nucleoside reverse transcriptase inhibitors (NRTI) are highly effective anti-HIV agents, viral resistance limits their therapeutic longevity. Resistance to 3'-azido, 3'-deoxythymidine (AZT) arises from phosphorolytic excision of the incorporated NRTI, which enables continued viral DNA synthesis. This excision is catalysed by reverse transcriptase (RT) and is enhanced by specific mutations in RT termed TAMs, or thymidine analogue mutations. Most highly drug experienced patients are infected with TAM-HIV and it is increasingly apparent that TAMs impact on resistance to other NRTI as well. Specific inhibitors of phosphorolytic excision could be very useful therapeutically by preventing the removal of incorporated NRTI, thereby restoring activity of NRTI such as AZT against TAM-containing HIV-1. Optimally, such inhibitors should not reduce incorporation of the NRTI during reverse transcription, which would antagonize their antiretroviral activity. We have identified certain bisphosphonates (BPH) as selective inhibitors of NRTI excision. BPH-218 inhibits RT-catalysed ATP-dependent and PPi- dependent excision of AZTMP in vitro (IC₅₀≈ 2 µM, but has minimal potency against RT-catalysed DNA synthesis (IC₅₀>50 µM), showing that BPH-218 is selective for inhibition of phosphorolysis. BPH-218 alone is only weakly active against replication of TAM-HIV (EC₅₀≈50 µM). However, when BPH-218 and AZT are added in combination, significant enhancement of antiviral activity is noted. As an example, AZT is only marginally active against TAM-HIV (EC₅₀≈3.5 µM compared to 0.3 µM against wild-type virus). In the presence of 50 µM BPH-218, the antiviral activity of AZT against TAM-HIV is dramatically increased (EC₅₀≈0.05 µM), suggesting that BPH-218 restores activity of AZT against this virus. BPH-218 also enhances activity of AZT against wild-type HIV-1, implying that NRTI excision is a factor in replication of wild-type virus in the presence of NRTI. Molecular modeling suggests that BPH-218 may compete with ATP and/or PP_i for binding to RT. BPH may represent a new class of antiviral adjuvant agents with potential clinical utility for the treatment of NRTI-resistant HIV infection.

This work was supported in part by NIH AI52010 and AI60452 (to MAP).

PRESENTING AUTHOR: MA Parniak

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2004-06-08
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