Diketo Acids Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and the Reverse Transcriptase RNase H Domain
Roberto Di Santo
Istituto Pasteur - Fondazione Cenci Bolognetti,
Dipartimento di Chimica e Tecnologie del Farmaco,
“Sapienza” University of Rome
P.le Aldo Moro 5, I-00185, Rome, Italy
Abstract:
HIV-1integrase (IN) is an essential enzyme for viral replication and mediates the insertion of the viral cDNA (generated by reverse transcription of the viral RNA) into the host cell genome. IN has emerged as an attractive target because it is necessary for stable infection and there is no known mammalian homologue of IN.
Reverse transcriptase (RT) is another multifunctional important HIV-1 enzyme that has polymerase and ribonuclease H (RNase H) activities, consisting in the degradation of RNA in RNA-DNA hybrid molecules that is required at several steps during the reverse transcription process, and is essential for retroviral replication.1
Some diketo acid inhibitors of HIV-1 IN have shown anti-RNase H activities. Thus, the simultaneous inhibition of HIV-1 IN and RT RNase H activities appears as a novel and attractive therapeutic way.
In the last decade we designed and synthesized a number of IN inhibitors.2,3 Among them the pyrrolyl diketo acid RDS 1643 was identified, which inhibited also the RT RHase H function.4 Design and synthesis and biological activities of analogues of RDS 1643 hit will be described.
References
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Tramontano E, Di Santo R et al Antiviral Res.2005, 65, 117.
