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The Stereoselective Targeting of a Specific Enzyme-Substrate Complex Is the Molecular Mechanism for the Synergic Inhibition of HIV-1 Reverse Transcriptase by (R)-(â)-PPO464
The human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor pyrrolopyridooxazepinone (PPO) derivative, (±)-PPO294, was shown to be active toward wild type and mutated HIV-1 RT and to act synergistically in combination with 3â²-azido-3â²-deoxythymidine (Campi...
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Published in: | The Journal of biological chemistry 2001-11, Vol.276 (48), p.44653-44662 |
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Main Authors: | , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor pyrrolopyridooxazepinone
(PPO) derivative, (±)-PPO294, was shown to be active toward wild type and mutated HIV-1 RT and to act synergistically in combination
with 3â²-azido-3â²-deoxythymidine (Campiani, G., Morelli, E., Fabbrini, M., Nacci, V., Greco, G., Novellino, E., Ramunno, A.,
Maga, G., Spadari, S., Caliendo, G., Bergamini, A., Faggioli, E., Uccella, I., Bolacchi, F., Marini, S., (1999) J. Med. Chem. 42, 4462â4470). The (±)-PPO294 racemate was resolved into its pure enantiomers, and the absolute configuration was determined
by x-ray analysis. Only one enantiomer, ( R )-(â)-PPO464, displayed antiviral activity against both the wild type and the K103N mutant HIV-1 RT and was found to interact
exclusively with the reaction intermediate formed by RT complexed with both the DNA and the nucleotide substrates. Being the
first compound of its class to display this behavior, (R)-(â)-PPO464 is the representative of a novel generation of nonnucleoside
inhibitors. (R)-(â)-PPO464 showed significant synergism when tested in combination with other RT inhibitors and efficiently
inhibited viral replication when tested against the laboratory strain HIV-1 IIIB or against either wild type or multidrug-resistant
clinical isolates. Pharmacokinetic studies in mice and rats showed a more favorable profile for (R)-(â)-PPO464 than for the
corresponding racemate. (R)-(â)-PPO464 was also found to easily cross the blood-brain barrier. The coadministration of the
HIV-1 protease inhibitor ritonavir increased the bioavailability of (R)-(â)-PPO464, having little effect on its plasma and
brain elimination rates. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M106702200 |