Design and synthesis of new inhibitors of HIV-1 protease dimerization with conformationally constrained templates

To inhibit the HIV-1 protease dimerization necessary to exhibit enzymatic activity, we synthesized and evaluated a new β-sheet peptide (compound 1), containing 4-(2-aminoethyl)-6-dibenzofuranpropionic acid as a conformationally restricted linker and a non-peptidic β-strand mimetic, 2-[3-({2-[(9-fluorenylmethoxy)carbonyl]hydrazino}carbonyl)-4-methoxyanilino]-2-oxoacetic acid (Fmoc-Hao-OH, compound 2). Kinetic analysis showed that compound 1 inhibited the dimerization of HIV-1 protease by a dissociative mechanism with a Kid value of 5.4 μM at 37° C (pH 5.0). However, compound 2 showed a small shift in the slope of the lines in the Zhang–Poorman plot (Kid=9.1 μM), suggesting that compound 2 inhibits the dimerization of HIV-1 PR not only through a dissociative mechanism but also through an active-site directed mechanism partly. This is the first study of a non-peptidic inhibitor of HIV-1 protease dimerization.