Retro-inverso

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. 

Berman JM, Goodman M, Nguyen TM-D, Schiller PW. Cyclic and acyclic partial retro-inverso enkephalins mu receptor selective enzyme resistant analogs. Biochem Biophys Res Commun 1983 115 864-870. 

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. 

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 ... 

Figure 11 van t Hoff Plots for the Synthetic L-a-Polypeptide H2N-DDALYDDKNWDRAPQRCYYQ-C02H (1) (A and C) and Its retro-inverso D-a-Isomer H2N-QYYCRQPARDWNKDDYLADD-C02H (2) (B and D) for MeCN/H20 (A and B) and the MeOH/H20 (B and D) Mobile-Phase Systems Containing 0.09% TFA at Different ijj Values[31 b... 

Figure 20 Plots of the Experimentally Observed Electromobilities, for L-a-Polypeptide 1, its retro-inverso D-a-Isomer 2, and the Synthetic Analogues 3-5 over the pH Range 2.0 < pH < 6.0l307 a,b...

Figure 21 Intrinsic Electrophoretic Mobility Contributions to the Total Mobility, Ptotal, of Each Charged Form of the L-a-polypeptide 1 and Its retro-inverso D-a-Isomer 2, Computed According to the Derived Values of the Molar Fraction, %, of the Different Charged Forms Corresponding to the +4, +3, +2,...,-2 Species and Equations 55-59 (adapted from Hearn, Keah, Boysen, Cassiano, Messana, Rossetti, and Castagnola,1 171 with permission)...

Draw three residues of a polypeptide chain constructed of L-amino acids using the top template of the two below. Now, using the second template, whose polypeptide chain begins at the right, use the same three residues, numbering from the C-terminus using D-amino acids. This is know as a retro-inverso polypeptide. 

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 ... 

What possible value can you imagine for retro-inverso polypeptides in design of drugs See Brady and Dodson, Nature 368, 692-694 (1994) or Guichard et al, Proc. Natl. Acad. Sci. USA 91, 9765-9769 (1994)... 

Preparation of [NHCHj] pseudodipeptides from a A-acetyl gem-diamine 88 and an a-aldehydo ester 89 was unsuccessful.185 The desired pseudodipeptide was unstable and eliminated the acetamide moiety. To overcome this instability a pseudotripeptide was prepared that incorporates the reduced retro isostere from a retro-inverso pseudodipeptide 85 the synthesis of this compound is shown in Scheme 16. Coupling of Z-L-Phe-OH with 32 using the mixed anhydride method afforded the retro-inverse pseudodipeptide 33. Reaction of 33 after hydrogenation with an a-aldehydo ester provides the reduced-retro pseudotripeptide 35 as a pair of diastereomers. 

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 ... 

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 ... 

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... 

The introduction of retro-, retro-inverso-, and PMRI-peptides with free and blocked C-and N-termini has been successful in numerous biological systems such as neurotransmitters, inhibitors of proteases and protein kinases, sweeteners, antimicrobial peptides, hormones, adhesion molecules, antigenic epitopes, immuno-modulators, and immunological probes. Table 1 provides an exhaustive list of retro-, retro-inverso-, PMRI-, and end-group-modified re/ro-mvmo-pseudopeptides derived from bioactive peptides. 

Table 1 Bioactive retro-, retro-inverso-, Partially Modified retro-inverso-, and End-Group-Modified retro-in-...

We have reviewed this class of retro- and retro-inverso-peptide analogues previously.1[2 3 72] Since then, Fletcher and Campbell 73 have published a comprehensive review on PMRI-peptides. It also covers a wide range of synthetic methodologies related to the synthesis of substituted malonates and gem-diaminoalkyl residues. 

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