Linear peptides

The intermediate (a) can also be arrived at directly from the unprotected linear peptide by applying the mixed anhydride method. After addition of one equivalent of acid, e.g. trifluoroacetic acid, the amino group will be protonated and the (still deprotonated) carboxyl anion will react with alkyl chloroformate to form (a), X = CO—O—Aik. Very conveniently, carbodiimides can be reacted with linear peptides unprotected at both ends to form cyclic peptides in satisfactory yields [26]. Since the carbodiimide method, particularly in the presence of V-hydroxybenzotriazole, is causing little racemization (see p. 93) this system is preferred in most laboratories. 

For the existence of a cyclic tripeptide one prohne together with two a-amino acids can be sufficient M. Rothe succeeded in the preparation of cyclo (Pro-Val-Val), yet not by cyclization of the corresponding linear tripeptide but by the insertion reaction of L-proline into the diketo-piperazine of l-valine [6]. For cyclotripeptide-cyclol equilibrium see page 197. 

In linear tetrapeptides for the ends to meet, only one of the four peptide bonds needs to have the c/s-configuration. Thus the exclusive presence of imino acids is not essential, cyclic tetrapeptides were found in nature even with exclusively a-amide bonds. R.O. Studer in 1969 synthesized the natural fungisporin, cyclo-(D-Val-L-Val-D-Phe-L-Phe) [28]. When discussing cyclization of pentapeptides, we shall come back to the doubling reaction and to gramicidin S. 

Preparation of cyclic peptides from linear hexapeptides and from longer ones does not offer special problems. Such compounds occur in great numbers in Nature. Some of them exhibit conspicuous biological activities these became the subject of investigation of the molecular mechanism of their interaction with receptors and of their conformations. The mechanisms of their biosynthesis are also extremely interesting. 

Elucidation of the biosynthesis of gramicidin S and of tyrocidin (Fig. 12), an additional component in Dubos tyrothricin, represents an important period in the development of our understanding of biochemistry. It took place at the time when the mechanism of protein-biosynthesis had just been recognized. In the 1950s, P. Zamecnik discovered that the synthesis of proteins in the cell occurs in organelles, later designated as ribosomes. Then M. Hoagland found a type of RNA, the transfer RNAs (t-RNAs) to which, in the presence of ATP, amino acids are attached in activated form. H.G. Zachau, G. Acs and F. Lipmann identified the mode of activation as esters of an adenosin residue in the t-RNA [30]. 

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The second application of the CFTI approach described here involves calculations of the free energy differences between conformers of the linear form of the opioid pentapeptide DPDPE in aqueous solution [9, 10]. DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen, where D-Pen is the D isomer of /3,/3-dimethylcysteine) and other opioids are an interesting class of biologically active peptides which exhibit a strong correlation between conformation and affinity and selectivity for different receptors. The cyclic form of DPDPE contains a disulfide bond constraint, and is a highly specific S opioid [llj. Our simulations provide information on the cost of pre-organizing the linear peptide from its stable solution structure to a cyclic-like precursor for disulfide bond formation. Such... 

The two /3-turn structures, pc and Pe are the most stable among those considered. This is in accord with the unconstrained nanosecond simulations of linear DPDPE, which converged to these conformers [14]. Because the cyclic form is relatively rigid, it is assumed that the conformation it adopts in solution is the biologically active one, responsible for its high affinity and specificity towards the 5 opioid receptor. The relatively low population of the cyclic-like structure for the linear peptide thus agrees qualitatively with the... 

The Cyc conformer represents the structure adopted by the linear peptide prior to disulfide bond formation, while the two /3-turns are representative stable structures of linear DPDPE. The free energy differences of 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. 

Figure 8 A joint principal coordinate projection of the occupied regions in the conformational spaces of linear (Ala) (triangles) and its conformational constraint counterpart, cyclic-CAla) (squares), onto the optimal 3D principal axes. The symbols indicate the projected conformations, and the ellipsoids engulf the volume occupied by the projected points. This projection shows that the conformational volume accessible to the cyclic analog is only a small subset of the conformational volume accessible to the linear peptide, (Adapted from Ref. 41.)...

Class IIHLA molecules are expressed on the surface of antigen-presenting cells. They play a key role in presentation of processed linear peptide antigens of at least nine amino acids to T cells. Antigen is bound to the HLA antigen binding cleft formed by the a and 3 chains of the HLA class II molecule. This tri-molecular HLA-antigen complex binds in turn to the variable portion of the T-cell receptor. 

Blanco FJ, Jimenez MA, Herranz J et al (1993) Nmr evidence of a short linear peptide that folds into a beta-hairpin in aqueous-solution. J Am Chem Soc 115 5887-5888... 

Fig. 21. Peptide-based glycoclusters at the wedge of linear peptide sequences or as cyclic scaffolds.

Demchuk E., Bashfoed D. and Case D. A. Dynamics of a type VI reverse turn in a linear peptide in aqueous solution. Fold. ... 

The influence of backbone flexibility was seen, for example, when the stability of the linear tetrapeptide 6.70 was compared to that of a cyclic hexa-peptide derivative of the same sequence [91]. Indeed, the cyclic peptide was approximately one order of magnitude more stable than the linear peptide in the pH range of 2-7. The results at higher pH values were inconclusive since the stability of the cyclic peptide decreased dramatically due to the degradation of a disulfide bond absent in the linear peptide. 

S—S—) appears to have some specific compact structure, but also gives evidence of structural softness (Epand, 1972a,b). The N-terminal tridecapeptide of RNase A appears to contain only a few percent o-helix (Brown and Klee, 1971). From this very small collection of linear peptides, it appears that the lower size limit for a stable compact structure is in the range of 20 and 40 residues. This agrees with estimates that can be made from consideration of surface/volume ratios as a function of peptide size (Rose and Wetlaufer, 1977). 

Because conformational epitopes are not easily mimicked with linear peptides, which can elicit nonspecific antibodies, several alternative strategies such as synthetic cyclic peptides have been developed [see e.g., (18)]. A similar conformational restriction was seemingly achieved with a P-amyloid peptide that was anchored to the surface of liposomes via hydrophobic tails introduced at its both N- and C-termini. The reconstituted peptide proved highly immunogenic and elicited antibodies that could significantly prevent amyloid plaque formation in a model system (70). 

Peptide and protein drugs must be transported without metabolic degradation to the systemic circulation in order to exhibit or exert their pharmacological action. Although active transport of linear peptides and oligopeptides by intestinal oligopeptide transporters has been reported, overall intestinal absorption of peptides is very poor because of metabolic degradation by peptidases. " ... 

Many medicinally useful peptides have cyclic structures. Cyclization may result if the amino acids at the two termini of a linear peptide link up to form another peptide bond. Alternatively, ring formation can very often be the resnlt of ester or amide linkages that utilize side-chain functionalities (CO2H, NH2, OH) in the constituent amino acids. 

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