Miniaturized Proteins: The backbone cyclic proteinomimetic approach

The field of proteinomimetics utilizes peptide-based molecules to mimic nat ive protein functions. We describe a novel general method for mimicking pro teins by small cyclic peptides for the purpose of drug design, and demonstr ate its applicability on bovine pancreatic trypsin inhibitor (BPTI). These unique cyclic peptides, which both embody discontinuous residues of protein s in their bio-active conformation and ensure an induced fit, may overcome some of the pharmacological drawbacks attributed to proteins and peptides. This method, which we call the backbone cyclic (BC) proteinomimetic approac h, combines backbone cyclization of peptides with a suitable selection meth od, cycloscan. Following this procedure, we have prepared a bicyclic nonape ptide, which mimics the binding region of BPTI. The X-ray crystal structure of the complex trypsin:mimetic, as well as kinetic studies, show that the BPTI mimetic binds to the specificity pocket of trypsin in a similar manner to BPTI. Inhibition measurements of various constructs revealed that backb one cyclization imposed the conformation crucial to binding. (C) 1999 Acade mic Press.