Peptides, p turns

In an attempt to design the p-turn-peptide-mimics, aspartic acid (an amino acid also known as aspartate) and lysine (an amino acid especially found in gelatin and casein) were attached to each amine group of 1,3-diaminoada-mantane in the form of amide bonds. The term p-turn refers to a peptide chain that forms a tight loop such that the carbonyl oxygen of one residue is hydrogen... 

Based on previously performed studies on p-turn peptides for asymmetric acylation reactions, the group of Miller expanded the application of such catalysts to the asymmetric conjugate addition of azides to a,p-unsaturated carbonyl compounds (Scheme 13.9a). A screening of several p-turn containing peptides disclosed catalyst 10 as the appropriate catalyst for the preparation of a series of p-azido-pyrrolidinone-derived imides in good yields and with enantioselectivities up to 85%. The obtained products can be further processed towards N-Boc-protected p-amino acids. Subsequent... 

All X-Pro peptide bonds—where X represents any residue—are synthesized in the trans configuration. However, of the X-Pro bonds of mature proteins, approximately 6% are cis. The cis configuration is particularly common in P-turns. Isomerization from trans to cis is catalyzed by the enzyme proline-CM,tr(2 r-iso-merase (Figure 5-9). 

Figure 2.7 (a) The P-bend or p-turn is often found between two stretches of antiparallel p-strands. (b) It is stabilized in part by hydrogen bonding between the C=0 bond and the NH groups of the peptide bonds at the neck of the turn... 

Moreover incorporation of a-methylproline into a peptide to replace proline in a p-turn... 

Secondary structures are regions of the peptide chain with a defined conformation (see p. 68) that are stabilized by H-bonds. In insulin (2), the a-helical areas are predominant, making up 57% of the molecule 6% consists of p-pleated-sheet structures, and 10% of p-turns, while the remainder (27%) cannot be assigned to any of the secondary structures. 

If the dominant conformation of the cyclic peptide is already known, the tendency for p-turns can, at least to a certain extent, be exploited to bring the termini of the linear precursor into closer proximity. Correspondingly, the peptide bond in/+ // +2-position usually is a bad choice, whereas the peptide bond i+2li+3 often represents one of the best cyclization sites (Scheme 5). 

In principle every compound with an amino and a carboxy group can be used for such purpose ranging from simple co-amino acids [e.g., 5-aminopentanoic acid (6-aminovaleric acid) (1, n = 3)]1541 or 6-aminohexanoic acid (e-aminocaproic acid) (1, n = 4)]135,57,4 791 and related derivatives of 3-aminobenzoic acid 14801 or more sophisticated structures. A few examples (1-6) are shown in Scheme 28. Numerous cyclic turn mimetics have been developed in the past years and for details on this subject the reader is directed to Vol. E 22c, Section 12. To explore the rigidification introduced by nonnatural amino acids or equivalent structures into cyclic peptides, a careful NMR conformational analysis is required, since frequently the so-called p-turn mimetics do not enable such turns to be established, conversely other secondary structure elements may be induced.14811... 

The next three sections (Sections 7.7.1, 7.7.2, and 7.7.3) cover fluorescence spectroscopy, I15-18 infrared, and circular dichroism, three powerful approaches to characterize the structure and conformational considerations of synthetic peptides. Section 7.7.1 deals with the use of fluorophores and broad aspects of fluorescence spectroscopy to characterize conformational aspects of peptide structure. In a similar manner, Section 7.7.2 covers a broad aspect of the uses of infrared (IR) techniques to study peptide conformations 19-22 Many IR techniques are discussed, as are approaches for the study of specific peptidic structures including amyloid, p-turn, and membrane peptides. Finally, there is a section on circular dichroism (Section 7.7.3) that covers the major issues of concern for peptide synthetic chemists such as the assignments of a-helix, 310-helix, -sheets and P-turns, and polyproline helices 23-25 There is also a brief description of cyclic peptides. 

The type III j8 turn is similar to a type I turn but has the ( ), angles of a 310 helix and the two chains emerging from the turn are not as nearly parallel as they are in type I turns. Beta turns of the less common types Y, IT, and III have a left-handed twist. As can be seen in Fig. 2-24, this permits a better match to the twist of strands in a P sheet. Unless glycine is present, these bends are less stable because of steric hindrance.214 215 Polar side chain groups such as those of aspartate or asparagine often form hydrogen bonds to the central peptide units of P turns.214... 

In a separate study, compounds 10A and 10B were incorporated into the gastrin peptide sequence, replacing the Tyr12-Gly13, to provide a potent analogue. 60 These data were used to imply an Alan-Trp14 p-turn in the bioactive conformation of gastrin. 

Spiro lactam 15 (Scheme 9), a dipeptide mimic with C (/)<-+Na(/ + l) cyclization, was used to replace the Pro-Tyr segment of an immunogenic peptide. 69 Comprehensive conformational analysis led to the conclusion that a type-II p-turn conformation was adopted in solution. 

Volume E 22 12.1 Synthesis of Peptides Incorporating P-Turn Inducers and Mimetics... 

Scheme 11 p-Turn Peptidomimetics and Their Incorporation into Peptide Sequences 74-76-78 ... 

Scheme 43 Preparation of Cyclic Peptides as p-Turn Peptidomimeticst1591...

Scheme 48 Bicyclic p-Turn Peptidomimetic and Its Incorporation into a Cyclic Peptide,165l...

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