A NOVEL BICYCLIC ENZYME-INHIBITOR AS A CONSENSUS PEPTIDOMIMETIC FOR THE RECEPTOR-BOUND CONFORMATIONS OF 12 PEPTIDIC INHIBITORS OF HIV-1 PROTEASE

The X-ray crystal structures of 12 substrate-based peptidic inhibitors bound in the active site of the aspartyl protease, HIV-1 protease, ha ve been compared. The inhibitor-binding modes of these inhibitors are remarkably similar despite their structural diversity and conformation al flexibility, This prompted the design of a bicyclic peptidomimetic inhibitor 13 with macrocyclic components in constrained conformations that are preorganized for receptor-binding. This inhibitor is a consen sus conformational mimic of the protease-bound inhibitor structures wi th superior properties to peptides, including stability to acid and pe ptidases as well as antiviral activity. Each of its 15- and 16-membere d rings, formed through side-chain to backbone condensation, contains two proteolytically resistant amide bonds and either isoleucine or val ine linked via a short aliphatic spacer to tyrosine, The two cycles ar e connected by a hydroxyethylamine transition state isostere. Molecula r modeling and NMR studies indicate that each macrocycle is a highly c onstrained structural mimic of tripeptide components of linear peptide substrates/inhibitors of HIV-1 protease. Thus the bicyclic peptidomim etic superimposes upon and structurally mimics acyclic hexapeptide inh ibitors and their analogues. This results in functional mimicry, as de monstrated by comparable inhibition of HIV-1 protease by acyclic and c yclic molecules at nanomolar concentrations. The rational design of cy cles which fix receptor-bound conformations of these bioactive peptide s has potential applications for the structural mimicry of other bioac tive peptides and may facilitate rational drug design.