Pentacycloundecane-diol-Based HIV-1 Protease Inhibitors: Biological Screening, 2D NMR, and Molecular Simulation Studies

Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild‐type C‐South African (C‐SA) HIV‐1 protease. Seven compounds are reported herein, three of which displayed IC50 values in the 0.5–0.6 μM range. The cytotoxicity of PCU cage peptides toward human MT‐4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through‐space 1H,1H distances/contacts in the EASY‐ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU‐based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases. Cage peptides unleashed: The combination of drug design with in vitro assays, NMR techniques, and molecular modeling has enabled us to rationalize the observed inhibitory activities toward HIV protease by the various cage peptides in this series. EASY‐ROESY NMR data show that the entire range of inhibitors exhibit a relatively stable interaction between the cage side chain and the cage protons.