Specific targeting of highly conserved residues in the HIV-1 reverse transcriptase primer grip region. 2. Stereoselective interaction to overcome the effects of drug resistant mutations.
Starting from the prototypic compound 4, we describe new, potent, and broad-spectrum pyrrolobenzo(pyrido)oxazepinones antivirals. A biochemical and enzymological investigation was performed for defining their mechanism of inhibition at either recombinant HIV-1 RT wild type and non-nucleoside reverse transcriptase inhibitors (NNRTIs)-resistant mutants. For the novel compounds (S)-(+)-5 and (S)-(-)-7, a clear-cut stereoselective mechanism of enzyme inhibition was found. Molecular modeling studies were performed for revealing the underpinnings of this behavior.
Butini
Stefania
S
Dipartimento Farmaco Chimico Tecnologico, Universita di Siena, via Aldo Moro 2, 53100 Siena, Italy.
Brindisi
Margherita
M
Cosconati
Sandro
S
Marinelli
Luciana
L
Borrelli
Giuseppe
G
Coccone
Salvatore Sanna
SS
Ramunno
Anna
A
Campiani
Giuseppe
G
Novellino
Ettore
E
Zanoli
Samantha
S
Samuele
Alberta
A
Giorgi
Gianluca
G
Bergamini
Alberto
A
Di Mattia
Michela
M
Lalli
Silvana
S
Galletti
Bruno
B
Gemma
Sandra
S
Maga
Giovanni
G
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D017124:Conserved Sequence; D004351:Drug Resistance / Q000187:drug effects* / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase