The Stereoselective Targeting of a Specific Enzyme-Substrate Complex Is the Molecular Mechanism for the Synergic Inhibition of HIV-1 Reverse Transcriptase by (R)-(−)-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 3′-azido-3′-deoxythymidine (Campi...

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Published in:The Journal of biological chemistry 2001-11, Vol.276 (48), p.44653-44662
Main Authors: Maga, Giovanni, Ramunno, Anna, Nacci, Vito, Locatelli, Giada A., Spadari, Silvio, Fiorini, Isabella, Baldanti, Fausto, Paolucci, Stefania, Zavattoni, Maurizio, Bergamini, Alberto, Galletti, Bruno, Muck, Sandra, Hubscher, Ulrich, Giorgi, Gianluca, Guiso, Giovanna, Caccia, Silvio, Campiani, Giuseppe
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container_end_page 44662
container_issue 48
container_start_page 44653
container_title The Journal of biological chemistry
container_volume 276
creator Maga, Giovanni
Ramunno, Anna
Nacci, Vito
Locatelli, Giada A.
Spadari, Silvio
Fiorini, Isabella
Baldanti, Fausto
Paolucci, Stefania
Zavattoni, Maurizio
Bergamini, Alberto
Galletti, Bruno
Muck, Sandra
Hubscher, Ulrich
Giorgi, Gianluca
Guiso, Giovanna
Caccia, Silvio
Campiani, Giuseppe
description 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 3′-azido-3′-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, 4462–4470). The (±)-PPO294 racemate was resolved into its pure enantiomers, and the absolute configuration was determined by x-ray analysis. Only one enantiomer, ( R )-(−)-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)-(−)-PPO464 is the representative of a novel generation of nonnucleoside inhibitors. (R)-(−)-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)-(−)-PPO464 than for the corresponding racemate. (R)-(−)-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)-(−)-PPO464, having little effect on its plasma and brain elimination rates.
doi_str_mv 10.1074/jbc.M106702200
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title The Stereoselective Targeting of a Specific Enzyme-Substrate Complex Is the Molecular Mechanism for the Synergic Inhibition of HIV-1 Reverse Transcriptase by (R)-(−)-PPO464
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