Conformation of cyclic peptides. Principle concepts and the design of selectivity and superactivity in bioactive sequences by 'spatial screening'

The description of small cyclic peptide conformations can be simplified by substitution of the peptide bond for an olefinic structure, which then is converted into a single bond (for the E configuration) or a pseudo-CH,-group (for Z olefins). The resulting cycloalkane conformations are related to the observed cyclic peptide structures. The individual conformation, however, is strongly influenced by the array of chirality in the peptide sequence. This can be used for a "spatial screening" of biologically active peptide sequences. The procedure is demonstrated on selective and highly active inhibitors for a,p3 integrins with a strong potential for development into anticancer drugs. Introducth Peptides play an important role in many biologically relevant processes and are of outstanding interest in pharmaceutical research. Locking the active conformation in cyclic peptides can give superpotent analogues in matched cases (1). In addition conformational constraints provide the basis for receptor selectivity; often different receptors bind the same flexible substrate in different conformations. We will present a new way to design selectivity and superactivity by "spatial screening". However, firstly we want to discuss the conformations of small cyclic peptides based on conformations of cycloalkanes. This reduction (Fig. 1) is done in the following way: The peptide bond is substituted by a carbon-carbon double bond (E or Z) yielding an olefin. According to Dunitz and Waser (2,3), the conformational behavior can be further reduced by substitution of a E double bond by a chemical bond and of a Z double bond by a pseudo-CH2-group. For example, 1,5-cyclooctadiene yields a rigid chair and a flexible boat conformation analogous to cyclohexane. Fig. 1 Schematic description of the exlension of lhe DUNlTZWASER concept lo peptides. of Cvclic Peptides and Cvcloalkanes To verify this concept, cyclic peptide structures were taken from the Cambridge Structural Database (CSD) (4). Metal coordinated cyclic peptides were omitted. The analogy of cyclic tripeptides containing three cis peptide bonds with cyclonona-l,4,7-triene and cyclohexane has been previously discussed (5, 6) and forms the basis for this work for the analysis of larger ring cyclic peptides.