Identification of Highly Potent Human Immunodeficiency Virus Type‑1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine

The emergence of
drug-resistant HIV from a widespread antiviral
chemotherapy targeting HIV protease in the past decades is unavoidable
and provides a challenge to develop alternative inhibitors. We synthesized
a series of allophenylnorstatine-based peptidomimetics with various
P3, P2, and P2́ moieties. The
derivatives with P2 tetrahydrofuranylglycine (Thfg) were
found to be potent against wild type HIV-1 protease and the virus,
leading to a highly potent compound 21f (KNI-1657) against
lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures
of 21f and the wild-type protease revealed numerous key
hydrogen bonding interactions with Thfg. These results suggest that
the strategy to design allophenylnorstatine-based peptidomimetics
combined with Thfg residue would be promising for generating candidates
to overcome multidrug resistance.