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R. Di Santo - Pyrrolyl diketo hexenoic acid derivatives as novel anti-HIV agents
H domain similarly to BTDBA (Klumpp &
Mirzadegan, Curr. Pharm. Des. 2006, 12:1909-22).
However, RDS1643 would not reach towards the p51
subunit as far as BTDBA, showing therefore a less
favourable interaction with RT, consistently with the
lower potency of RDS1643 inhibition as compared to
BTDBA inhibition (Tramontano et al., Antiv. Res.
2005, 65:117-24; Klumpp & Mirzadegan, Curr. Pharm.
Des. 2006, 12:1909-22). Other DKA derivatives, structurally
similar to BTDBA and RDS1643, but lacking
inhibitory activity against the HIV-1 RNase H function,
were also modelled into the RNAse H active site
showing steric hindrance with its domain; this data fitted
with the lack of their biological activity.
Since RDS1643 was originally designed as HIV-1
IN inhibitor (Di Santo et al., Farmaco 2005, 60:409-
17), a few RDS1643 derivatives were synthesized by
our research group in the last year and were assayed
on both HIV-1 RT-associated enzyme activities. The
data coming form the enzyme assays showed that
introduction of substituents in 4-position of the
benzyl ring of RDS1643 did not affect the interaction
with the biological target giving compounds
with inhibitory potency comparable to that of
RDS1643. This is consistent with the proposed
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model of interaction between RDS1643 and the
HIV-1 RNase H active site.
Selected pubblications
Di Santo R, Costi R, Roux A, Miele G, Crucitti GC,
Iacovo A, Rosi F, Lavecchia A, Marinelli L, Di
Giovanni C, Novellino E, Palmisano L, Andreotti M,
Amici R, Galluzzo CM, Nencioni L, Palamara AT,
Pommier Y, Marchand C. Novel quinolinonyl diketo
acid derivatives as HIV-1 integrase inhibitors:
design, synthesis, and biological activities. J Med
Chem. 2008, 51:4744-50.
Jegede O, Babu J, Di Santo R, McColl DJ, Weber J,
Quiñones-Mateu M. HIV type 1 integrase inhibitors:
from basic research to clinical implications. AIDS
Rev. 2008, 10:172-89.
Terrazas-Aranda K, Van Herrewege Y, Hazuda D,
Lewi P, Costi R, Di Santo R, Cara A, Vanham G.
Human immunodeficiency virus type 1 (HIV-1) integration:
a potential target for microbicides to prevent
cell-free or cell-associated HIV-1 infection.
Antimicrob Agents Chemother. 2008, 52:2544-54.