Retro peptides

Goodman M, Chorev M. (1979) On the concept of linear modified retro-peptide structures. Acc Chem Res 12 1-7. 

Structural isomers of pentapeptide 1A and tripeptide 8 are represented in Scheme 1. For pentapeptide 1A, its retro-peptide 6A, enantiomer (all-D-peptide) IB, retro-inverso-peptide (all-D-retro-peptide) 6B, partially modified, retro-inverso-peptide 7, end-group-modified, partially modified, retro-inverro-peptides 2-4, and end-group-modified, retro-inverso-pep-tide 5 are shown. For end-group-blocked tripeptide 8, its retro-peptide 13, end-group-modified, partially modified, retro-inverso-peptides 9-11, and end-group modified retro-inverso-peptide 12 appear. 

The retro-peptide bond is a true isosteric peptide bond surrogate and as such may offer an important tool to study topics such as the functional role of the peptide backbone in peptide hormone-receptor interactions, and modulation of metabolic stability and bioavailability. Partially modified retro-inverso-peptides (PMRI-peptides) (e.g., 2-4, 7 Scheme 1) result from a retro-inverso transformation of one or several peptide bonds in an amino- and carboxy-free peptide (e.g., 5 Scheme 1). Evidently, partial or exhaustive retro-inverso transformations result in the introduction of two non-amino acid residues into the... 

One approach is simply to use D-amino acids, which peptidases may not recognize. Unfortunately, neither does the intended receptor much of the time. Another involves reversing the peptide sequence so that, for example, H-Phe-Leu-Ser-NH2 becomes H-Ser-Leu-Phe-NH2- These are the so-called retro peptides. Combining both of these, called the retro-inverso approach, produces molecules where the amide bond has been inverted (HNCO in place of CONH) while the sidechains are presented in a similar way as they were... 

See Chorev, M., Goodman, M. Recent developments in retro peptides and proteins - An ongoing topochem-ical exploration. Trends Biotechnol. 1995, 13, 438-445. 

Influence of the peptide bond between AAj and AA2 residues. iV-methylation of the peptide link in the dipeptides Phe-Gly, Phe-Ala or Phe-Leu, leads to a 100-fold reduction in inhibitory activity indicating that the amide group is hydrogen bonded to the active site of the enzyme [78]. Support for this now comes from the observation that a retro-peptide bond in Phe-Ala reduces inhibitory activity 10-fold. Whereas there is only a modest loss of inhibitory activity in (i )-thiorphan (thiol analogue of the dipeptide Tyr-Gly), there is a 100-fold loss in activity in the (.S)-isomer of retrothiorphan (see Table 6.6) [90]. 

Mery J., Brugidou Rabie A. A peptide nucleic acid (PNA) is more rapidly internalized in cultured neurons when coupled to a retro-inverso delivery peptide. The antisense activity depresses the target mRNA and protein in magnocellu-lar oxytocin neurons. Nucleic Acids Res. 

Guichard, G., Briand, J. P., Muller, S., Cung, M. T. Structure of antibody-bound peptides and retro-inverso analogues. A transferred nuclear Overhauser effect spectroscopy and molecular dynamics approach. Biochemistry 2001, 40, 5720-5727. 

Stem, P. S., M. Chorev, M. Goodman, and A. T. Hagler. 1983. Computer Simulation of the Conformational Properties of Retro-Inverso Peptides. II Ab Initio Study, Spatial Electron Distribution, and Population Analysis of N-Formylglycine Methylamide, N-Formyl N -Acetyldiaminomethane, and N-Methylmalonamide. Biopolymers 22, 1901-1917. 

Figure 4 Retro-inversion of host defense peptides. Synthesis of RI peptides is achieved by substituting o-amino acids at all stereocenters within a peptide and reversal of peptide sequence (RI - R3 in the i-peptide and R3 RI in the Rl-peptide). By rotating the Rl-peptide at 180° it can be seen that the three-dimensional space occupied by the amino acid functional (R) groups is retained in comparison to the i-peptide although the peptide backbone has been reversed.

In contrast, Snyder has demonstrated that an RI derivative ofp53 can restore endogenous p53 activity the RI derivative induced apoptosis by activation of endogenous p53 and by restoration of function to several p53 DNA contact mutants. Rl-modified peptides have also been investigated as potential alternatives for bost defense peptides. Indeed, a RI derivative of indolicidin retained tbe antimicrobial and antiendotoxic acitivities of the natural peptide. As the antiendotoxin activities of the Rl-derivative were conserved these results might indicate the conservation of multiple immunomodulatory activities upon retro-inversion, highlighting the potential of this modification for therapeutic applications. 

Synthesis. The synthesis of cyclo retro enantlcxner 6 Is outlined in Scheme 1. Compounds 4, 5, 7> and 9 were prepared by an analogous route. Initially, a protected linear hexapeptide was prepared by solid phase synthesis on 2% crossllnked polystyrene resin beginning with a protected lysine resin. The peptide was then removed from the polymer by hydrazlnolysis. Cycllzatlon was... 

As with the cyclo retro isomers, these studies have shown that there may be more than one peptide backbone conformation which can produce similar side chain topography. The N -methyl lysine analogs have also further confirmed that the n -H of lysine has no important role in receptor binding or conformational stabilization. These compounds did not, however, provide any advantage over 3 in biological selectivity or duration of action. 

After the sulfation of alcohols and phenols was reported to proceed efficiently with DCC/ H2S04, 75 76 Wieland et al. 81 applied this procedure for the sulfation of the tyrosine residue in D-Tyr6-a//-D-retro-antamanide. This contains no reactive group in addition to the phenolic group, and the desired product was obtained in satisfactory yields. Despite these promising initial results, this type of sulfation reaction has been adopted only sporadically, e.g. for sulfation of the CCK-8 derivative Boc-Asp(OtBu)-Tyr-Met-Gly-Trp(For)-Met-Asp-(OtBu)-Phe-NH2 with 70% yield1 2 or for the preparation of an intermediate fragment in the synthesis of CCK-related peptides (Scheme 3). 83 ... 

The conformational properties of cyclic hexapeptides have been extensively investigated over decades by the use of suitable model systems.1137-288 With appropriate peptide sequences the phenomena of cycloenantiomerism and cyclodiastereomerism have been defined 289,290 and reverse turns have been classified for model ring structures. 206 Similarly, the retro-inverso concept was established for the first time with cyclic hexapeptides 130 in this context it is noteworthy that the total retro-inverso structure of a cyclic peptide is especially easy to synthesize, as it does not require specific building blocks but only inverted chirality and full-sequence reversal. 265 ... 

Compare the outer surface of of the standard polypeptide and its retro-inverso analog. How would your answer be affected by the presence of threonine or isoleucine in the peptides ... 

The retro-inverso concept1133 was adopted to examine the synthesis and conformational properties by X-ray diffraction analysis of retro-sulfonamide i [NH—SOJ peptide analogues, t134 ... 

Scheme 30 Synthesis of the Retro-sulfonamido Peptide Boc-Pro-Leui [NH-S02]Gly-NH/l34l...

The combination of the nonpalindromic nature of the peptide backbone and the chirality of the a-carbons in the amino acids comprising the oligomeric structure provides a unique opportunity for vast stereochemical and topochemical diversities. Earlier studies explored the interesting structural relationship between all-L-, retro-all-L-peptides, and their enantiomers (see reviews[1 3]). Schematically, a high degree of topochemical complementarity is obtained between parent cyclic peptides and their retro-inverso analogues.11 ... 

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