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.
