Heterocyclic-based peptidomimetics

Abstract

Heterocyclic-based peptidomimetics possess properties that are dictated by the chemical and physical properties of the constituent heterocycle. Here we review two general classes of peptidomimetic, one in which the conformation of a peptide is confined into a particular geometry, and a second, where chemical reactivity is masked and released in a controlled manner. We have used the aromatic heterocycles, pyrrole and tetrazole, to mimic the geometry of cis-peptide bonds and peptide bond isosteres. A tetrazole-based hydroxyethylamine isostere, which mimics a bioactive cis-like geometry of JG365 as bound to HIV protease, has been developed and shown to provide the basis of conformationally constrained inhibitors of this enzyme. A number of other simple tetrazole-based molecular scaffolds are also discussed. The second section of this review discusses how the inherent reactivity of a hydroxymethylpyrrole can be masked with the introduction of an electron withdrawing group on nitrogen. The selective removal of this group then releases a highly reactive species. Compounds of this type have been shown to inhibit α-chymotrypsin.