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: A novel generation of nonnucleoside inhibitors

Giovanni Maga, Anna Ramunno, Vito Nacci, Giada A. Locatelli, Silvio Spadari, Isabella Fiorini, Fausto Baldanti, Stefania Paolucci, Maurizio Zavattoni, Alberto Bergamini, Bruno Galletti, Sandra Muck, Ulrich Hubscher, Gianluca Giorgi, Giovanna Guiso, Silvio Caccia, Giuseppe Campiani

Research output: Contribution to journalArticle

Abstract

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)-(-)-PP0464 than for the corresponding racemate. (R)-(-)-PP0464 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.

Original languageEnglish
Pages (from-to)44653-44662
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number48
DOIs
Publication statusPublished - Nov 30 2001

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of '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: A novel generation of nonnucleoside inhibitors'. Together they form a unique fingerprint.

  • Cite this