Pseudopeptide bonds

J. P. Meyer, T. J. Gillespie, S. Horn, V. J. Hruby, T. P. Davis, In vitro Stability of Some Reduced Peptide Bond Pseudopeptide Analogues of Dynorphin A , Peptides 1995, 16, 1215-1219. 

Meyl995 Meyer, J.-R, Davis, R, Lee, K.B., Rorreca, F, Yamamura, H.I. and Hruby, V.J., Synthesis Using a Fmoc-Based Strategy and Biological Activities of Some Reduced Peptide Bond Pseudopeptide Analogues of Dynorphin A, J. Med. Chem., 38... 

In peptide chemistry, the term "pseudopeptide" is commonly used to denote a peptide in which some or all of the amino acids are linked together by bonds other than the conventional peptide Linkage (13). Such pseudopeptides have found applications as specific structural... 

The present chapter focuses on specific aspects of these challenges, namely peptide bond hydrolysis (chemical and enzymatic) and intramolecular reactions of cyclization-elimination (Fig. 6.4). This will be achieved by considering, in turn a) the enzymatic hydrolysis of prodrugs containing a peptide pro-moiety (Sect. 6.2), b) the chemical hydrolysis of peptides (Sect. 6.3), c) the enzymatic hydrolysis of peptides containing only common amino acids (Sect. 6.4), d) the hydrolysis of peptides containing nonproteinogenic amino acids (Sect. 6.5), and, finally, e) the hydrolysis of peptoids, pseudopeptides and peptidomimetics (Sect. 6.6). 

Pseudopeptides are not always clearly defined in the literature. Here, we use the term to mean compounds with a modified peptide backbone, namely with some or all peptide bonds replaced by bioisosteric surrogates. 

As stated above, we define pseudopeptides as compounds having a modified peptide backbone, namely with at least one peptide bond replaced by a bioisosteric surrogate (summarized in Table 6.7) [139][181][234], Such surrogate groups are nonhydrolyzable by nature, or hydrolyzable only under severe conditions in the case of the S02-NH bond. In the vast majority of published pseudopeptides, only one or a very few peptide bonds had been replaced and most monomeric units are amino acids, meaning that such pseudopeptides do qualify as peptides. 

Table 6.7. Examples of R-CONH-R Peptide-Bond Surrogates Used in Pseudopeptides... 

G. J. Anderson, Incorporation of Stable Pseudopeptide Bonds , in Methods in Molecular Biology, Neuropeptide Protocols , Eds. G. B. Irvine, C. H. Williams, Humana Press, Totowa NJ, 1997, p. 49-60. 

Y. Crozet, J. J. Wen, R. O. Loo, P. C. Andrews, A. F. Spatola, Synthesis and Characterization of Cyclic Pseudopeptide Libraries Containing Thiomethylene and Thiomethy-lene-sulfoxide Amide Bond Surrogates , Mol. Discov. 1998, 3, 261-276. 

D. E. Benovitz, A. F. Spatola, Enkephalin Pseudopeptides Resistance to in vitro Proteolytic Degradation Afforded by Amide Bond Replacements Extends to Remote Sites , Peptides 1985, 6, 257 - 261. 

Scheme 27 Igloo-shaped tetramacrocyclic pseudopeptides with 20 amide bonds in a defined three-dimensional arrangement synthesized by the MiBs strategy in one-pot...

These complex macrobicycles were assembled by the incorporation of eight more building blocks, forming 12-24 new bonds in a one-pot reaction. The more complex three-dimensional multi-macrocyclic pseudopeptides like the igloos might in principle be considered mimics of internally disulfide bridged crumpled proteins like the knottins (Scheme 27) [101]. 

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. 

A reduced peptide bond can be obtained either in soln or by solid-phase synthesis. The aldehyde of the N -protected a-amino acid reacts with the a-amino function of the C-protected a-amino acid or peptide, to yield a Schiff base 17 which is reduced to give the pseudopeptide 18 (Scheme 10). 

As indicated in Scheme 14, introduction of the rp[CH(CN)NH] peptide bond surrogate into pseudopeptides 28 is carried out via a modified asymmetric Strecker synthesis by the Lewis acid catalyzed reaction of N -protected a-amino aldehydes 26 with a-amino esters 27.11791... 

The first synthesis of r j[NHCH2] containing pseudopeptides was described in 1989. This reduced retro-amide bond isostere was presumed by molecular graphic analysis to provide potential protease inhibitors. A complete study of the conformational effects by modifying the amide link with [NHCHj] was reported. 86,871... 

Due to the good nucleophilic nature of sulfur, formation of new C—S bonds is relatively easy. This property has been used for intramolecular peptide cyclization 1 and was exploited for preparation of methylenethio ether surrogates, t >[CH2—S], initially as peptide gap inhibitors for blocking collagenase action. 2 These surrogates were later converted into sulfoxide and sulfone derivatives. This expansion of amide replacements compelled a more generalized nomenclature system for pseudopeptides (amides with one or more amide bond surrogates) and led directly to the psi-bracket convention. 1 ... 

Each methylenethio unit adds three daltons to the peptide weight compared to the parent amide. Mass spectrometry can both confirm the expected mass as well as demonstrate preferred cleavages at both C—S bonds. In a linear pseudopeptide N-terminal or C-terminal fragments allow partial characterization of the location and sequence of the replacement by identification of the fragments using positive and negative ionization, respectively.t56 ... 

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