Peptide retro-inverso

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. 

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... 

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. 

Solid-Phase Synthesis of Partially Modified retro-inverso Peptides... 

The degradation of support-bound a-amino acid amides has been used to prepare retro-inverso peptide mimetics ([226], second equation in Figure 10.6). These compounds are of interest because of their potentially improved metabolic stabilities, selectivities, and biological activities compared with peptides [226], Although retro-inverso peptides are aminals susceptible to acid-catalyzed hydrolysis, N,N -diacylated aminals can be sufficiently stable to withstand the conditions of Boc-group removal [227] or of acidolytic cleavage of peptides from Wang resin [226]. 

Fletcher, M. D., Campbell, M. M. Partially Modified Retro-Inverso Peptides Development, Synthesis, and Conformational Behavior. Chem. Rev. 1998, 98, 763-796. 

The 1,1-diaminoalkane derivatives such as 113, developed as a new class of sweet peptides by Goodman et al. 238) on the basis of the retro-inverso peptide modification 20), are 800-1000 times as sweet as sucrose. 

Retropeptides contain the —NHCO— group and when the adjacent amino acids have the d configuration the structural resemblance to the related l peptide is quite close. Moreover, such retro-inverso peptides are stable to hydrolysis by pro-teinases. 

A totally retro-inverso peptide is an isomer of a linear peptide in which the direction of the amino acid sequence is reversed and the chirality at the C carbon of the residues is inverted. This modification has been widely applied [83]. Antigenicity and immunogenic-ity have been demonstrated by preparation of retro-inverso isomers of natural antigenic peptides [84], Retro-inverso forms derived from mellitin and cercropin A maintain antimicrobial activity [85]. A cyclic retro-enantiomeric D amino acid peptide has been designed and shown to be active as synthetic inhibitor of the interaction between immunoglobulin E (IgE) and its high-affinity receptor FceRl [86]. 

Finally, we shall emphasize the successful developments of retro-in-verso (all-D-retro) and end group-modified retro-inverso peptides in several biological areas including hormones [104,105], antibody recognition [106-109], peptide vaccines [110], MHC class II presentation [111,112], protein surface and receptor mimicry [113-115], antibacterial and channel-forming peptides such as mellitin and cecropin A [116,117], intracellular delivery systems [118], and nuclear import [119]. 

We have extensively investigated the extent of antigenic mimicry achievable with retro-inverso peptides and evaluated their potential in the development of peptide-based vaccines [106,110]. We designed and synthesized using Fmoc//Bu chemistry an end group-modified retro-inverso analogue 38 of the foot-and-mouth disease virus (FMDV) major antigenic site located within residues 141-159 of the viral VPl protein (Fig. 4) [110,135]. 

Antilla et al synthesized a novel phosphoric acid derivative (48), starting from (R)-VAPOL (vaulted biphenanthrol) [181], and demonstrated its catalytic activity in the addition of sulfonamide to aldimines, giving rise to protected aminals, which have been incorporated into peptide chains as retro-inverso peptide mimics. (Scheme 2.105) [182]... 

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