Pentapeptides

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 structures of higher peptides follow in an analogous fashion Figure 27 7 gives the structural formula and ammo acid sequence of a naturally occurring pentapeptide... 

For this FAB experiment, a sample of the pentapeptidic enkephalin, Tyr.Gly.Gly.Phe.Leu., dissolved in glycerol was bombarded by xenon atoms. The resulting mass spectrum shows abundant protonated molecular ions at m/z 556. 

Pentapeptide consisting of five amino acid residues (A-E)... 

Evidence soon emerged that the endogenous opioids were peptides rather than simple morphine-like molecules (9). The first direct evidence for endogenous opioids in brain extracts was provided in 1975 when two pentapeptides were purified that differed only in the carboxyl terminal amino acids (10) (Table 1). These peptides were called methionine- (Met-) and leucine- (Leu-) enkephalin, from the Greek term meaning "in the head."... 

When the compounds of interest are fragile and thermally labile, thermospray Ic/ms is a good choice. Figure 5, shows the thermospray spectmm for leucine enkephalin [58822-25-6] a pentapeptide of molecular weight 555. The Ic/ms approach has been very helpful in unraveling the stmcture of large biological molecules (21). 

One component of the age-ielated decline in immune function is decreased production of the lymphokine that promotes the growth of T-ceUs, interleukin 2 (IL-2). Administration of recombinant-derived IL-2, both in vitro and in vivo, appears to restore certain immune functions in aged mice. Recovery of T-regulatory effects on B-ceU differentiation has been reported in human cells from elderly patients treated with IL-1 and/or IL-2 (42). Similar effects have been observed in the presence of the pentapeptide thymopentin [69558-55-0] (Arg Lys Asp Val Tyr), a weU-known IL-2 inducer. Recombinant IL-2 adrninistered to aged mice for three weeks has been shown to correct the T-ceU functional deficiency associated with antigen-specific immunoglobulin production by certain lymphoid tissue (43). 

The conformation an amino acid adopts depends on the residues in its neighborhood. This was made clear from a study of identical pentapeptides in unrelated proteins which were observed to adopt the same conformation only 20% of the time (24). The effect that residues neighboring in sequence or in space have on the conformation is not well understood. 

Synergy has been reported between lL-1, lL-3, and SCE, ki enhancing the survival of lethaHy kradiated mice engrafted with 2 x 10 BM cells and immediately given cytokiaes once daily for five days (173). SCE alone does not enhance survival, and lL-1 or lL-3 has limited effect. Pretreatkig mice with thymopentki, a synthetic pentapeptide derivative of thymopoietin, enhances the protective effect of lL-1 a, as kidicated by 30-day survival (174). 

Almost all actinomycins have the same chromophore, a planar phenoxa2inone dicarboxyUc acid called actinocin. In dactinomycin, the stmcture of which is shown in Figure 12, the two pendent pentapeptide lactones are identical, but in other actinomycins these lactones may be different. In other actinomycins the first amino acid, amide linked with actinocin, is usually L-threonine, as in dactinomycin the second position is sometimes D-aHo-isoleucine instead of D-valine the third position may be sarcosine or oxoproline the fourth position is sarcosine and the fifth position is sometimes /V-methyl isoleucine instead of /V-methylvaline. The lactone ring is always present. 

The enzymes gyrase and topoisomerase IV can be protected from fluoroquinolone inhibition by a small protein belonging to the pentapeptide-repeat family of... 

The macrocyclization of a peptide was carried out by nucleophihc substitution on a fluorobenzene by the sulfide group of the terminal cysteine of a pentapeptide [164]. The peptide 261 was prepared by standard SPPS and was cyclized under microwave irradiation at 50 °C for 10 min in DMF (Scheme 96). The yields of 262, after cleavage with TFA, were remarkably high for a macrocyclic peptide (70%) and also the resulting HPLC purity was very high. 

Nodularia spwnigena has also been shown to produce a peptide with hepato-toxic activity. The more recent reports come from Australia (76), the German Democratic Republic (77), Denmark (78), Sweden (79), and Finland (80,81). Recently structure information on Nodularia toxin has been presented by Rinehart (97) for waterbloom material collected in Lake Forsythe, New Zealand, in 1984 by Eriksson et al. (81) from waterbloom material collected in the Baltic Sea in 1986, and Runnegar et al. (82) for a field isolate from the Peel Inlet, Perth, Australia. Structure work by Rinehart, Eriksson, and Runnegar all indicate that the peptide is smaller than the heptapeptide toxins. Rinehart s work (97) indicates the toxin is a pentapeptide with a similar structure to the heptapeptides and containing fi-methylaspartic acid, glutamic acid, arginine, dehydrobutyrine, and ADDA (MW 824). 

Several results are quite apparent from the data shown in Table II. It is evident from the pentapeptide model compounds that substitution of amino acid residues at positions 4 and 5 does not significantly affect the structure about the N-terminus. This observation corroborated earlier work from agglutination-inhibition assays, which demonstrated that the nature of the amino acid at position 4 of the peptide (or glycopeptide) is not a requirement for specificity. 

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