Peptide analog design conformational approach

In an effort to overcome some of these difficulties and to provide the beginnings of a rational approach to the design of hormone analogs, we have utilized conformational and topographical restriction of peptide hormone and neurotransmitter structures. In this approach, we have attempted to make use where possible of classical structure-function studies, to Interpret the results from these studies In terms of specific conformational parameters which may be Involved In the observed rela-... 

Thus, the monofluoroalkene moiety is a non-hydrolysable isostere of the pep-tidic bond, and hence can be used as a peptidomimetic unit in the design of protease inhibitors [59,60]. This type of rigid isosteres of the peptidic bond can facilitate the cisjtrans conformational control of the fragment replaced. Because of the double bond, the bond length and angles of the peptidic bond are suitably mimicked, and the fluorine atom complements the analogy for electronic properties. This approach has been developed in the case of prolylamide fragments, in... 

Phosphonopeptides containing a transition state analog of the hydrolysis of the amide bond represent another attractive approach for the preparation of proteolitically stable peptides (10,30,31). In addition to increased stability, incorporation of a phosphonate moiety into the peptide sequence provides access to additional binding interactions within the transition-state conformation of the enzyme/substrate complex (13). This peptidomimetic approach is used to design very effective protease inhibitors (31-34). As in the case... 

MMMS) 200 These techniques turned out to be a valuable tool for the design of conformational constrained analogs of biolc cally active molecules. These compounds, e.g. cyclic peptides 6.203,204) possess an artifically introduced restriction of their conformational flexibility by modifying the peptide backbone. This approach allows a more detailed investigation of the influence of the conformation on biological activity. 

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