TY - JOUR
T1 - Miniaturized proteins
T2 - The backbone cyclic proteinomimetic approach
AU - Kasher, Ron
AU - Oren, Deena A.
AU - Barda, Yaniv
AU - Gilon, Chaim
PY - 1999/9/17
Y1 - 1999/9/17
N2 - The field of proteinomimetics utilizes peptide-based molecules to mimic native protein functions. We describe a novel general method for mimicking proteins by small cyclic peptides for the purpose of drug design, and demonstrate its applicability on bovine pancreatic trypsin inhibitor (BPTI). These unique cyclic peptides, which both embody discontinuous residues of proteins 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 approach, combines backbone cyclization of peptides with a suitable selection method, cycloscan. Following this procedure, we have prepared a bicyclic nonapeptide, 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 backbone cyclization imposed the conformation crucial to binding.
AB - The field of proteinomimetics utilizes peptide-based molecules to mimic native protein functions. We describe a novel general method for mimicking proteins by small cyclic peptides for the purpose of drug design, and demonstrate its applicability on bovine pancreatic trypsin inhibitor (BPTI). These unique cyclic peptides, which both embody discontinuous residues of proteins 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 approach, combines backbone cyclization of peptides with a suitable selection method, cycloscan. Following this procedure, we have prepared a bicyclic nonapeptide, 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 backbone cyclization imposed the conformation crucial to binding.
KW - Backbone cyclic peptides
KW - Backbone cyclization
KW - Bovine pancreatic trypsin inhibitor
KW - Cycloscan
KW - Proteinomimetic
UR - http://www.scopus.com/inward/record.url?scp=0033578941&partnerID=8YFLogxK
U2 - 10.1006/jmbi.1999.3053
DO - 10.1006/jmbi.1999.3053
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C2 - 10493885
AN - SCOPUS:0033578941
SN - 0022-2836
VL - 292
SP - 421
EP - 429
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 2
ER -