Novel PCU cage diol peptides as potential targets against wild-type CSA HIV-1 protease: synthesis, biological screening and molecular modelling studies

We have synthesized a series of novel pentacycloundecane cage diol diacid (PCU diol diacid) incorporated C (2)-symmetric peptides. Their activity against the resistance-prone wild-type C-South African (C-SA) HIV protease (HIV PR) is reported. These compounds were obtained in moderate yields of 42-72 \%. Amongst the nine compounds reported herein only compound 6, 7, 10 and 11 showed moderate IC50 values of 5-10 mu M. Peptides 7 and 10 contain two phenylglycine and two tryptophan amino acids, respectively as side arms to the cage diol. Phenylglycine is a non-natural amino acid. Docking and molecular dynamics (MD) studies were carried out to understand the binding mode of the PCU moiety at the active site of the HIV PR enzyme. The computational results show that the cage diol peptide fits quite comfortably inside the active site of the enzyme. Not much movement is observed during the MD simulation and the hydrogen bonds that develop between the inhibitor and the enzyme pocket suggest that the inhibitor/HIV PR complex is stable at room temperature.