title: Synthesis and biological activity of potent HIV-1 protease inhibitors based on Phe-Pro dihydroxyethylene isosteres.
abstract: Peptidomimetic inhibitors of HIV-1 PR are still a key resource in the fight against AIDS. Here we describe the synthesis and biological activity of HIV-1 PR inhibitors based on four novel dihydroxyethylene isosteres of the Phe-Pro and Pro-Pro dipeptides. The isosteres, containing four stereogenic centers, were synthesized in high yield and excellent stereoselectivity via the cyclization of epoxy amines derived from α-amino acids. The inhibitors were assembled by coupling the isosteres with suitable flanking groups and were screened against recombinant HIV PR showing activities in the subnanomolar to micromolar range. Two Phe-Pro-based inhibitors active at the nanomolar level were further investigated: both inhibitors combine the ability to suppress HIV-1 replication in infected MT-2 cells with low cytotoxicity against the same cells, thereby displaying a high therapeutic index. These results demonstrate the potential of the new Phe-Pro dihydroxyethylene isostere as a core unit of powerful HIV-1 PR inhibitors.
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Trieste, via Giorgieri 1. 34127 Trieste, Italy. benedett@units.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Benedetti
authors.forename: Federico
authors.initials: F
authors.lastname: Berti
authors.forename: Sara
authors.initials: S
authors.lastname: Budal
authors.forename: Pietro
authors.initials: P
authors.lastname: Campaner
authors.forename: Francesca
authors.initials: F
authors.lastname: Dinon
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tossi
authors.forename: Radka
authors.initials: R
authors.lastname: Argirova
authors.forename: Petia
authors.initials: P
authors.lastname: Genova
authors.forename: Vasil
authors.initials: V
authors.lastname: Atanassov
authors.forename: Anton
authors.initials: A
authors.lastname: Hinkov
mesh_terms: D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D010649:Phenylalanine / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D004151:Dipeptides; D017320:HIV Protease Inhibitors; C448039:prolyl-proline; D010649:Phenylalanine; D011392:Proline