Pentapeptides, cyclic, conformations

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... 

Since there is only a small energy difference between the different conformational states depending upon the presence or absence of a Pro, Gly or N-alkylated amino acid residue, and upon the chirality of the constituent amino acid residues and also to a lesser extent upon the side-chain functionalities, it is not possible to unambiguously predict the conformation of a cyclic pentapeptide. These molecules have often been studied in different solvents and solvent effects were neglected, and/or the methodology to handle such conformational equilibrium was not available. It is only recently that modem NMR techniques and computational procedures have become available to treat this complex problem of fast exchanging conformational equilibria. 36,269,270 ... 

The RGD sequence was thus constrained into a variety of sheet or /3-turn structures, which were unequivocally determined for each peptide. The biological activity of 18 cyclic peptides was then compared with that of a linear standard, GRGDS, in inhibition assays of tumour cell adhesion. An increase in activity of up to 100-fold was observed for just two cyclic pentapeptides, all others showing a decrease in activity. This identified the required conformation of the RGD backbone. 

Quite recently, we have described the seven-membered ring y-turn mimetic 25f45l (Scheme 16) designed to mimic a proposed bioactive conformation in the cyclic pentapeptide mal-formin family. The synthesis is depicted in Scheme 17. The compounds were tested in a relevant bioassay, but were devoid of activity. 

Morita H, Nagashima S, Takeya K, Itokawa H, Iitaka Y (1995) Structures and Conformation of Antitumour Cyclic Pentapeptides, Astins A, B and C, from Aster tataricus. Tetrahedron 51 1121... 

The hard-sphere potential has also been used to compute the sterically allowed conformations of small polypeptides of known amino acid sequence, viz. an octapeptide loop of ribonuclease (Nemethy and Scheraga, 1965) and the cyclic decapeptide gramicidin-S (Vanderkooi et al., 1966). We shall use the calculation for gramicidin-S to illustrate the method. This decapeptide consists of two identical pentapeptides joined into a ring by peptide bonds, the amino acid sequence being... 

Metaldi ef o . 112) nthesized a cyclic pentapeptide, Cyclo Qly-Ala-Gly-Gly Pro), and invest ted the 220-MHz NMR spectra in DMSO-d. Each proton gave two sets of resonance signals, so that the existence of two different conformations was considered, a nu r conformation being represented by M and a minor conformation by m. Hie chemical shift and the temperature dependence of the resonance signal, and die oinqparison with model peptides suggested the structures shown in Fig. 19... 

Very recently, Nakajima and Okawa 164) investigated the hydrolysis of PNPA by Cyclo-(His-Glu-Cys-D-Phe-Gly)2. The second-order rate constant for the hydrolysis at pH 7.73 and 25 C was 19.61 M min for the cyclic decapeptide diacetate, which wt(s larger than 6.05 min for the corresponding linear pentapeptide triacetate and 1.33 M min for histidine hydrochloride, but smaller than 32.20 M min for cystein hydrochloride. The pH-rate profile for the reaction catalyzed by the cyclic decapeptide was bell-shaped with the maximum around pH 7.6, which indicates that the cyclic decapeptide is an acid—bs catalyst. On the other hand, the reaction by the cyclic decapeptide obeyed the Michaelis-Menten kinetics (i57), wdiich was found to involve a weak binding of the substrate = 2.7xlO M) prior to the unimolecular step. It is possible for imidazole, carboxyl, and thiol functions to cooperate in the cat ysis by the cyclic decapeptide, but the determination of the solution conformation would not be an easy task because of the thirty mem-bered ring. 

FIGURE 15.10 (cont d). Conformations of the four different molecules of a cyclic pentapeptide [formula in (a)], per asymmetric unit (Ref. 62). (b) Views of the four symmetry-independent molecules in the asymmetric unit. Note the different orientations of the Leu and Val side chains. 

Porcelli, M., Casu, M., Lai, A., Saba, G., Pinori, M., Cappelletti, S. and Mascagni, P. (1999) Cyclic pentapeptides of chiral sequence DLDDL as scaffold for antagonism of G-protein coupled receptors synthesis, activity and conformational analysis by NMR and molecular dynamics of ITF 1565 a substance P inhibitor. Biopolym. 50 211-219. 

Dichotomins A, B, C, and E showed cell growth inhibitory activities against p388 lymphocytic leukemia cells (IC50 A 2.5 /xg/ml B 3.5 pg/ml C 5.0 /xg/ml E 2.0 jug/ml) dichotomin D did not. The amino acid sequences of dichotomins A, B, and C are the same, except at residue 5 (dichotomins A Val B Thr C Ala). The cyclic pentapeptide, dichotomin E, contains a sequence (Tyr-Ala-Phe) similar to the Phe-Leu-Tyr sequence present in dichotomins A, B, and C, the central aliphatic amino acid of which is sandwiched between two aromatic amino acids. This inhibitory activity may be due to the sequencing and/or conformation of these dichotomins. 

Conformations of Cyclic Pentapeptide Endothelin Receptor Antagonists. 

In cyclic dipeptides, the peptide groups are constrained to the cis conformation. Cyclic tripeptides also require cis peptide groups, whereas in cyclic tetra- and pentapeptides a transition takes place between a variety of confer-... 

---