Structural Analysis of Potent Hybrid HIV‑1 Protease Inhibitors Containing Bis-tetrahydrofuran in a Pseudosymmetric Dipeptide Isostere

The
design, synthesis, and X-ray structural analysis of hybrid
HIV-1 protease inhibitors (PIs) containing bis-tetrahydrofuran (bis-THF)
in a pseudo-C2-symmetric dipeptide isostere are described.
A series of PIs were synthesized by incorporating bis-THF of darunavir
on either side of the Phe-Phe isostere of lopinavir in combination
with hydrophobic amino acids on the opposite P2/P2′ position.
Structure–activity relationship studies indicated that the
bis-THF moiety can be attached at either the P2 or P2′ position
without significantly affecting potency. However, the group on the
opposite P2/P2′ position had a dramatic effect on potency depending
on the size and shape of the side chain. Cocrystal structures of inhibitors
with wild-type HIV-1 protease revealed that the bis-THF moiety retained
similar interactions as observed in the darunavir–protease
complex regardless of the position on the Phe-Phe isostere. Analyses
of cocrystal structures and molecular dynamics simulations provide
insights into optimizing HIV-1 PIs containing bis-THF in non-sulfonamide
dipeptide isosteres.