Pseudopeptides isosteres replacing peptide

Figure 15.17. Isosteres that replace peptide backbone amide groups to generate pseudopeptides.

Peptidomimetics are peptide molecules characterized by modifications to the side chain (Section 9), to the a-carbon (Sections 10.3 and 10.4), or, to the components of a peptide bond itself either singularly (e.g., Sections 10.1 and 10.2), or, in combination. Peptidomimetics containing a modification to the nature of the peptide bond are often referred to as pseudopeptides or peptide bond surrogates. 1 These compounds are sometimes termed as peptide bond isosteres, although the isosteric nature of the replacement is often not obvious or may even be dubious. 

The replacement of amide bonds by retro-in-verso amide replacements (71, 72) and other amide bond isosteres generates pseudopeptides (11). This process was first used to stabilize peptide hormones in vivo and later to prepare transition state analog (TSA) inhibitors. Systematic efforts to convert good in vitro inhibitors into good in vivo inhibitors became the driving force for further development of peptidomimetics. Figure 15.17 illustrates some of the peptide backbone modifications that have been made in an effort to increase bioavailability. Replacement of scissile amide (CONH) bonds with groups insensitive to hydrolysis (e.g., CHaNH) has been extensively practiced. Reviews of this work have appeared (11,73). Removal of the proton donors and... 

Replacement of the normal peptide bond (-CONH-) with an isosteric unit generally does not alter the overall dimensions of the modified peptide. The replacement unit is referred to as a pseudopeptide bond, and a peptide analogue containing the modified bond is referred to as a pseudopeptide. The symbol ip was originally introduced (43) with specific reference to the sulfur-based CH2S peptide bond replacement and was later used for various CH2S-containing... 

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