Peptide strands

Extended Peptide Strands, Turns and Formation of Sheet Structures... 

As mentioned in the introductory part of Section 2.2.3, fully extended y9-peptide strands can be generated by populating antiperiplanar conformations around the C a)-C fi) bond (0j values close to 180° Fig. 2.27A). 

Fig. 2.27 The two types of extended /1-peptide strands with conformation requirements around the C(a)-C(/1) bonds. (A) Parallel and antiparallel polar sheets with antiperiplanar conformations around the C(a)-C fl) bond are promoted by unlike-fi -ami-no acids with alkyl side-chains. Antiperiplanar side-chains at C(a) and C(/3) occupy positions approximately perpendicular to the amide planes. (B) Extended strands formed by alternating +)-sc and (-)-sc conformations...

To prevent insolubility resulting from uncontrolled aggregation of extended strands, two adjacent parallel or antiparallel yS-peptide strands can be connected with an appropriate turn segment to form a hairpin. The / -hairpin motif is a functionally important secondary structural element in proteins which has also been used extensively to form stable and soluble a-peptide y9-sheet arrangements in model systems (for reviews, see [1, 4, 5] and references therein). The need for stable turns that can bring the peptide strands into a defined orientation is thus a prerequisite for hairpin formation. For example, type F or II" turns formed by D-Pro-Gly and Asn-Gly dipeptide sequences have been found to promote tight a-pep-tide hairpin folding in aqueous solution. Similarly, various connectors have been... 

Furthermore, D- and L-prolyl-(l,l-dimefhyl)-l,2-diaminoethyl (Pro-DADME) segments have been used successfully to connect two y9-peptide strands via their C-termini and to promote the formation of a parallel hairpin (e.g. 123) in both solution (CD3OH) and solid state (Fig. 2.32) [196]. 

When tethered to structural units that may associate in more than one way, an H bonded duplex template will help specify the intermolecular interaction, leading to a single assembly. The possibility of directing the association of namral peptide strands was tested by using our H bonded duplexes as templates. 

Incorporation of the Dibenzofuran-4,6-dipropanoic Acid Template with Intervening Ethylene Glycol Units Between the Template and Peptide Strands... 

The nucleation of parallel (3-sheet structure via metal ion chelation in aqueous solution was investigated by incorporating an ethylene glycol spacer between a dibenzofuran-4,6-dipro-panoic acid template and the two peptide strands (Scheme 6).[7 The flexibility of the ethylene glycol spacer allows the peptide to sample a variety of largely unordered conformations in the absence of metal ions. Upon binding of palladium(II), nickel(II), or copper(II) ions, the peptidomimetic adopts a well-defined (3-sheet conformation as discerned from biophysical and spectroscopic studies (i.e., CD, IR absorption, and H NMR spectrometry).17 The synthesis of the dibenzofuran-4,6-dipropanoic acid template was discussed... 

Scheme 6 Incorporation of an Ethylene Glycol Spacer Between the Template and the Peptide Strands 1...

Several laboratories have described systems by which synthetic linear peptide chains self-assemble into desirable secondary and tertiary structures. One self-assembly approach has been the creation of a peptide-amphiphile, whereby a peptide head group has the propensity to form a distinct structural element, while a lipophilic tail serves to align the peptide strands and induce secondary and tertiary structure formation, as well as providing a hydrophobic surface for self-association and/or interaction with other surfaces. The preparation of a dialkyl ester tail first involves the acid-catalyzed condensation of H-Glu-OH with the appropriate fatty acid alcohol to form the dialkyl ester of H-Glu-OH a typical example is shown in Scheme 7. The assembly of peptide-amphiphiles with mono- and dialkyl ester tails is shown in Scheme 8. A series of studies have demonstrated that triple-helical and a-helical protein-like molecular architecture is stabilized in the peptide-amphiphile 44,63-65 ... 

To study the nucleation step for the folding of collagen, a protocol has been developed for the liquid-phase synthesis by which three peptide strands are covalently linked via a C-terminal branch. 70-73 The C-terminal branch is expected to enhance triple-helical thermal stability, and to provide a model of the disulfide-linked C-terminus of type III collagen. 71 ... 

The mono-esters thus prepared have been used by Bolm et al. for selective synthesis of two-stranded peptidic structures with parallel arrangement of the peptide strands [12]. They also enable easy access to unnatural /i-amino acids in enan-tiomerically pure form. The latter reaction sequence involves conversion of the carboxyl group to an acyl azide and subsequent Curtius degradation [11, 13, 14]. 

Furthermore, we could show that this reaction mechanism to produce Cp-complexes of "mTc is not limited to carboxylate derivatives of Cp but that also further functionalities can be conjugated to receive, e.g., amides (49 and 50) [125]. This reactivity implies that, comparable to the SAAC approach, Thiele s acid derivatives can be incorporated in, e.g., a peptide strand and directly be labeled with [99mTc(OH2)3(CO)3]+. The preparation of cyclopentadienyl complexes with a variety of functionalities attached to the cyclopentadienyl ring stands for a more routine introduction of this important tridentate ligand in radiopharmaceutical organometallic complexes. 

Oxazolidinones, such as linezolide, are a newly discovered drug group (p.281). They inhibit initiation of synthesis of a new peptide strand at the point where ribosome, mRNA, and the start-tRNA-AA complex aggregate. Oxazolidinones exert a bacteriostatic effect on Gram-positive bacteria. Since bone marrow depression has been reported, hematological monitoring is necessary. 

Click chemistry also found applications in peptides and peptidomimetics. Alkyne-azide cycloaddition between two peptide strands provided an efficient convergent synthesis of triazole ring-based P-tum mimics <07CC3069>. The synthesis of a-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected a-propynyl proline in the presence of Cu(I) sulfate <07SL2882>. The synthesis of new trifluoromethyl peptidomimetics with a triazole moiety has been reported <07TL8360>. 

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