This is an Abstract Submission for:
Marcella Facchini
Inst Molecular Genetics IGM-CNR, Univ. Pavia
Via Abbiategrasso 207
27100 Pavia
Italy
Tel.: +39 333 5791378
Fax: +39 0382 422286
Email: marcella.facchini@virgilio.it
Unique Abstract Identifier (UAI): 5793e5140705122433
Characterization of novel N,N-DABOs as effective tight binding non-nucleoside inhibitors of
HIV-1 RT
M. Facchini1, A. Samuele1, L. Ferrigno1, A. Karytinos1, D. Rotili2, A. Mai2, G. Maga1
1
Inst Molecular Genetics IGM-CNR, Univ. Pavia (Pavia);
2
Inst Pasteur, Dept Pharmaceutical Research, Univ. La Sapienza (Rome)
In this study we investigated some 2-chloro-6-fluoro analogs of N,N-dihydro-alkoxy-benzyloxopyrimidine derivatives (N,N-DABOs), previously described as effective HIV-1 reverse
transcriptase (RT) non-nucleoside inhibitors (NNRTIs), characterized by a broad activity spectrum
against NNRTIs resistant mutants. Our binding mode and kinetic analyses revealed that these novel
compounds inhibited all the enzymes tested (wt, K103N, Y181I) with higher efficacy, higher
association rates (kon) and lower dissociation rates (koff) than those 2,6 F2-substituted, which indicate a
tight binding mode of action for these derivatives to the non-nucleoside binding site (NNBS) of the
enzymes. In particular, the compound MC1839 exhibited major affinity to the ternary complex
formed by the viral enzyme with its nucleic acid and nucleotide substrates, being its koff values for this
latter complex markedly reduced compared to those evaluated for the other kinetic forms. These data
would be useful for further antiviral molecular modelling investigations
This is an Abstract Submission for:
Alessandra Amoroso
Inst Molecular Genetics IGM-CNR, Univ. Pavia
Via Abbiategrasso 207
27100 Pavia
Pavia
Italy
Tel.: +39 349 8312292
Fax: +39 0382 422286
Email: amoroso@igm.cnr.it
Unique Abstract Identifier (UAI): 52f4f0750705145539
Second generation PBOs show enantioselective binding to the catalytic complex of HIV-1 RT
wt and drug resistant mutants.
A. Amoroso1, A. Samuele1, G. Campiani2, A. Karytinos1, M. Facchini1, S. Zanoli1, G. Maga1
1
Inst Molecular Genetics IGM-CNR, Univ. Pavia (Pavia);
2
Dept of Pharmaceutical Chemical Technology and European Research Center for Drug Discovery
and Development, University of Siena (Siena)
In this study we investigated some analogs of pyrrolobenzoxazepinone derivatives (PBOs),
previously described as effective non nucleoside inhibitors of HIV-1 reverse transcriptase (RT), and
their corresponding R and S enantiomers, in order to evaluate their interactions with RT wild type
and the drug-resistant mutants K103N, L100I and V179D. Our results revealed that the R
enantiomers inhibited all the enzymes tested with higher efficacy than the corresponding S isomers,
indicating a stereoselective mode of action for these compounds. Moreover, steady state kinetic
analysis showed that PBOs exhibited selective ability to target the ternary complex formed by the
viral enzyme with its nucleic acid and nucleotide substrates. In particular, our analysis showed that
the compound PBO 1027 R was, unexpectedly, more active towards the mutant L100I than towards
the wt enzyme, whereas the compound PBO 1060 R inhibited the mutant K103N with comparable
potency to the wild type RT.