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PubMed1984

Atriopeptin release from the isolated perfused rabbit heart.

Mammalian atrial extracts have been shown to contain bioactive peptides which exert natruiretic, diuretic, and smooth muscle relaxant effects. These extracts include several low molecular weight (less than 5,000 Mr) atrial peptides (atriopeptins) which exhibit identical sequences over a central core region which are derived from the high molecular weight peptide (atriopeptigen) precursor which has been purified and sequenced. In the current study we found that extracts of rabbit atria possess both high and low molecular weight bioactive atrial peptides, however, the coronary venous effluent obtained from the isolated perfused rabbit heart only contained the low molecular weight peptide. This trypsin labile activity causes a dose-dependent relaxation of rabbit aorta and chicken rectum assay strips. Separation of the bioactivity with gel filtration chromatography and reversed phase HPLC indicates the heart releases a single substance similar to atriopeptin III. There was no evidence that atriopeptigen was released from the isolated perfused rabbit heart. We suggest that atriopeptigen is proteolytically processed in the atria to an atriopeptin which is subsequently the released form of the atrial peptide.

Animals↗

PubMed2006

[Purification and characterization of weak-acid antibacterial peptide MD7095 from Musca domestica larvae].

Musca domestica,which belongs to insecta, diptera, cyclorrhapha, muscidae, is the most common muscae and the richest resource. It is very significant and valuable to isolate antibacterial peptides from Musca domestica and to develop these peptides into antibacterial medicine. Due to purify a pure peptide from the natural materials (animal, plant and microorganism tissue) is very difficult and complex, few research is going on. It had been reported that the most antibacterial peptides from Musca domestica were alkaline, no weak-acid antibacterial peptides had been reported so far. Based on a high sensitivity detection method, using dilute acetic acid extraction, alginic acid absorption, NaCl salting-out, Sephadex G-25 gel filtration, CMC23 ion-exchange chromatography, electrophoresis, a group of weak-acid antibacterial peptides had been purified from Musca domestica larvae and partial characterized. The peptides had characters of broad antibacterial spectrum and low minimum bactericidal concentration against Gram-positive bacterium such as Bacillus thuringiensis, Bacillus subtilis, Staphylococcus aureus and Gram-negative bacterium such as Pseudomonas aeruginosa, Escherichia coli. The peptides were very stable to keep the antibacterial activity even kept in 95 degrees C for 120 min and frozen-thawed for 10 times. A weak-acid antibacterial peptide MD7095 had been purified in high degree of purity by electro-elution,and was determined Mr 7095Da with MALDI-TOF-MS and pl 5.59 with IEF-PAGE. Peptide mass fingerprinting (PMF) analysis showed MD7095 was a novel bioactive peptide. Few peptides with antibacterial activity against Bacillus thuringiensis had been reported. Observation by scanning electron microscopy (SEM), it was suggested that the bioactivity mechanism of antibacterial peptides from Musca domestica larvae against Bacillus thuringiensis was to perforate cell membrane and lead to bacterium lysis and die. It is hopeful to develop the antibacterial peptides from Musca domestica to candidate medicine.

Animals↗

PubMed2006

C-terminal amino acid residue loss for deprotonated peptide ions containing glutamic acid, aspartic acid, or serine residues at the C-terminus.

Deprotonated peptides containing C-terminal glutamic acid, aspartic acid, or serine residues were studied by sustained off-resonance irradiation collision-induced dissociation (SORI-CID) in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer with ion production by electrospray ionization (ESI). Additional studies were performed by post source decay (PSD) in a matrix-assisted laser desorption ionization/time-of-flight (MALDI/TOF) mass spectrometer. This work included both model peptides synthesized in our laboratory and bioactive peptides with more complex sequences. During SORI-CID and PSD, [M - H]- and [M - 2H]2- underwent an unusual cleavage corresponding to the elimination of the C-terminal residue. Two mechanisms are proposed to occur. They involve nucleophilic attack on the carbonyl carbon of the adjacent residue by either the carboxylate group of the C-terminus or the side chain carboxylate group of C-terminal glutamic acid and aspartic acid residues. To confirm the proposed mechanisms, AAAAAD was labelled by 18O specifically on the side chain of the aspartic acid residue. For peptides that contain multiple C-terminal glutamic acid residues, each of these residues can be sequentially eliminated from the deprotonated ions; a driving force may be the formation of a very stable pyroglutamatic acid neutral. For peptides with multiple aspartic acid residues at the C-terminus, aspartic acid residue loss is not sequential. For peptides with multiple serine residues at the C-terminus, C-terminal residue loss is sequential; however, abundant loss of other neutral molecules also occurs. In addition, the presence of basic residues (arginine or lysine) in the sequence has no effect on C-terminal residue elimination in the negative ion mode.

Amino Acid Sequence↗

PubMed2001

Isolation and characterization of the rat prolactin-releasing peptide gene: multiple TATA boxes in the promoter region.

The prolactin-releasing peptide (PrRP) gene is a novel bioactive peptide expressed in very restricted regions in the brain. To explore the molecular mechanism of PrRP gene expression, we cloned and characterized the gene and its promoter region. The gene spans approximately 2.4 kb and contains three exons and two introns. 3'RACE analysis showed that a polyadenylation signal 103 bp downstream from the stop codon was functional. Primer extension analysis indicated three transcriptional start sites (TSSs) 92, 199, and 325 bp upstream from the translational start site. Interestingly, in addition to the putative binding sites for SP1-1, AP-2, and Oct-2A, three characteristic TATA boxes were identified close to these TSSs. Transient transfection study using a series of deletion mutants revealed that the middle TATA box is important for the promoter activity. Furthermore, the cloned 1.6 kb promoter region was active only in neuron- and pituitary-derived cell lines, and the promoter region -1600 approximately -800 bp worked as a negative regulatory element. We demonstrated for the first time, the genomic organization and promoter function of the PrRP gene, and this knowledge will facilitate elucidation of transcriptional control of the PrRP gene.

3' Untranslated Regions↗

PubMed2000

Homodimeric peptides displayed by the major coat protein of filamentous phage.

Peptide libraries displayed by filamentous bacteriophage have proven a powerful tool for the discovery of novel peptide agonists, antagonists and epitope mimics. Most phage-displayed peptides are fused to the N terminus of either the minor coat protein, pIII, or the major coat protein, pVIII. We report here that peptides containing cysteine residues, displayed as N-terminal fusions to pVIII, can form disulfide-bridged homodimers on the phage coat. Phage clones were randomly selected from libraries containing one or two fixed Cys residues, and surveyed for the presence of peptide-pVIII homodimers by SDS-PAGE analysis that involved pretreatment of the phage with reducing or thiol-modifying agents. For all phage whose recombinant peptide contained a single Cys residue, a significant fraction of the peptide-pVIII molecules were displayed as dimers on the phage coat. The dimeric form was in greater abundance than the monomer in almost all cases in which both forms could be reliably observed. Occasionally, peptides containing two Cys residues also formed dimers. These results indicate that, for a given pVIII-displayed peptide bearing a single Cys residue, a significant fraction of the peptide (>40 %) will dimerize regardless of its sequence; however, sequence constraints probably determine whether all of the peptide will dimerize. Similarly, only occasionally do peptides bearing two Cys residues form intermolecular disulfide bridges instead of intramolecular ones; this indicates that sequence constraints may also determine dimerization versus cyclization. Sucrose-gradient analysis of membranes from cells expressing pVIII fused to a peptide containing a single Cys residue showed that dimeric pVIII is present in the cell prior to its assembly onto phage. A model of the peptide-pVIII homodimer is discussed in light of existing models of the structure and assembly of the phage coat. The unique secondary structures created by the covalent association of peptides on the phage surface suggest a role for homo- and heterodimeric peptide libraries as novel sources of bioactive peptides.

Amino Acid Sequence↗

PubMed1997

Identification and initial characterisation of a N-benzyloxycarbonyl-prolyl-prolinal (Z-Pro-prolinal)-insensitive 7-(N-benzyloxycarbonyl-glycyl-prolyl-amido)-4-methylcoumarin (Z-Gly-Pro-NH-Mec)-hydrolysing peptidase in bovine serum.

A group of enzymes exists that specifically recognises proline within proteins and peptides. Prolyl endopeptidase is one such enzyme, which cleaves on the carboxyl side of proline within peptide substrates. Its broad specificity towards bioactive peptides has led to its implication in various disease states including neurodegenerative and psychiatric disorders. This association has been based primarily on the abnormal levels of activity observed following the enzymes detection with the reportedly specific fluorimetric substrate, 7-(N-benzyloxycarbonyl-glycyl-prolyl-amido)-4-methylcoumarin (Z-Gly-Pro-NH-Mec). In this study, we report the discovery and preliminary characterisation of a Z-Gly-Pro-NH-Mec-hydrolysing activity that is distinct from prolyl oligopeptidase (prolyl endopeptidase). Following the production of serum from bovine whole blood, Z-Gly-Pro-NH-Mec hydrolysis in serum was determined to be 7.2 U/mg protein. In the presence of 350 nM Z-Pro-prolinal, a specific inhibitor of prolyl endopeptidase, residual Z-Gly-Pro-NH-Mec hydrolysis of 2.6 U/mg protein was observed. This residual activity was resistant to inhibition by Z-Pro-prolinal at concentrations in excess of 200 times its reported Ki value for prolyl endopeptidase and could not be inhibited under conditions of prolonged incubation with the inhibitor. Following cation-exchange chromatography, Z-Gly-Pro-NH-Mec-hydrolysing activity was resolved into two distinct entities. The first of these activities was inhibited by Z-Pro-prolinal, demonstrated activity towards the thyroliberin analogue, 7-(pyroglutamyl-histidyl-prolyl)-4-methylcoumarin (Glp-His-Pro-NH-Mec), and was catalytically enhanced under reduced assay conditions. This activity was subsequently designated prolyl endopeptidase. The second activity was totally resistant to Z-Pro-prolinal inhibition, demonstrated no activity towards Glp-His-Pro-NH-Mec, and was unaffected when assayed under reduced conditions. It was subsequently designated Z-Pro-prolinal-insensitive Z-Gly-Pro-NH-Mec-hydrolysing peptidase (ZIP).

Animals↗

PubMed2004

Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice.

Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently being explored as a new approach to the treatment of type 2 diabetes. This concept has emerged from the powerful and rapid action of the enzyme to inactivate glucagon-like peptide-1 (GLP-1). However, other bioactive peptides with potential influence of islet function are also substrates of DPP-4. Whether this inactivation may add to the beneficial effects of DPP-4 inhibition is not known. In this study, we explored whether DPP-4 inhibition by valine-pyrrolidide (val-pyr; 100 micromol/kg administered through gastric gavage at t = -30 min) affects the insulin and glucose responses to iv glucose (1 g/kg) together with GLP-1 (10 nmol/kg), glucose-dependent insulinotropic polypeptide (GIP; 10 nmol/kg), pituitary adenylate cyclase-activating polypeptide 38 (PACAP38; 1.3 nmol/kg), or gastrin-releasing peptide (GRP; 20 nmol/kg) given at t = 0 in anesthetized C57BL/6J mice. It was found that the acute (1-5 min) insulin response to GLP-1 was augmented by val-pyr by 80% (4.2 +/- 0.4 vs. 7.6 +/- 0.8 nmol/liter), that to GIP by 40% (2.7 +/- 0.3 vs. 3.8 +/- 0.4 nmol/liter), that to PACAP38 by 75% (4.6 +/- 0.5 vs. 8.1 +/- 0.6 nmol/liter), and that to GRP by 25% (1.8 +/- 0.2 vs. 2.3 +/- 0.3 nmol/liter; all P < 0.05 or less). This was associated with enhanced glucose elimination rate after GLP-1 [glucose elimination constant (K(G)) 2.1 +/- 0.2 vs. 3.1 +/- 0.3%/min] and PACAP38 (2.1 +/- 0.3 vs. 3.2 +/- 0.3%/min; both P < 0.01), but not after GIP or GRP. The augmented insulin response to GRP by val-pyr was prevented by the GLP-1 receptor antagonist, exendin(3) (9-39), raising the possibility that GRP effects may occur secondary to stimulation of GLP-1 secretion. We conclude that DPP-4 inhibition augments the insulin response not only to GLP-1 but also to GIP, PACAP38, and GRP.

Animals↗

PubMed1995

Cloning and characterization of the cDNA encoding the human neuromedin U (NmU) precursor: NmU expression in the human gastrointestinal tract.

Many peptide precursors encode more than one bioactive peptide. Recent cloning of the rat neuromedin U (NmU) precursor revealed potential proteolytic processing sites which may generate three associated peptides in addition to the NmU peptide, which is known to have potent uterine contractile effects. To assess the degree of evolutionary conservation, which often suggests conserved biological function and hence physiological importance, we have cloned and sequenced the cDNA encoding the human NmU precursor. Sequence analysis revealed a 174 amino acid human precursor containing the 25 residue NmU peptide near the C terminus of the precursor. The human message sequence was 74% homologous with that of the rat, indicating evolutionary conservation of the precursor between these two species. Four out of five of the putative proteolytic processing sites, first revealed in the rat precursor, were conserved in the human precursor, indicating a similar processing mechanism in both species. Two such processing sites flank a 33 residue peptide sequence which differed in only two amino acids compared with the rat homologue. This conservation suggests a possible biological role for this putative peptide. Northern blot analysis of human gastrointestinal tissues revealed a similar level of mRNA throughout the gastrointestinal tract. RIA using a porcine specific assay showed the highest levels of peptide in the jejunum samples.

Amino Acid Sequence↗

PubMedDate not supplied

Pulmonary gastrin-releasing peptide expression in anencephaly.

Gastrin-releasing peptide (GRP) is a developmentally regulated bioactive peptide believed to function as a pulmonary growth factor. It is produced by pulmonary neuroendocrine cells, found within the conducting and respiratory epithelium, as isolated cells and in clusters known as neuroepithelial bodies (NEBs). Deficient GRP expression has been reported in pulmonary hypoplasia (PH) associated with oligohydramnios and diaphragmatic hernia. To assess further the role of GRP in maldeveloped lung we reviewed the postmortem records and histologic lung sections, stained with H&E and anti-GRP antiserum, from 11 infants with anencephaly and 11 age-matched controls. Cells immunoreactive for GRP were quantified (isolated versus NEBs) in airways and airspaces per mm2 for a standard area. PH was present in five anencephalic infants. There was no difference in the total number of GRP-positive cells, number of NEBs, size of NEBs, or number of GRP-positive cells in airways or alveoli in either group regardless of lung development. A greater proportion of the GRP-positive cells was present in the airways in anencephalic infants with PH (58%) compared with anencephalic infants without PH (40%) (P = .018). There were no differences when comparing these groups with control infants and no differences in the density of airways in each of these groups. We conclude that deficient GRP expression is not a feature of lung hypoplasia in anencephalic infants. The altered distribution of GRP-positive cells in anencephalic infants with PH may be a reflection of the structural abnormalities or accompanying altered cellular maturity.

Anencephaly↗

PubMed1986

Cell-specific post-translational processing of preproglucagon expressed from a metallothionein-glucagon fusion gene.

Glucagon is a peptide hormone of 29 amino acids encoded by a preprohormone which contains in tandem the sequences of glucagon and two additional glucagon-like peptides (GLPs) structurally related to glucagon and separated by intervening peptides. Glucagon arises by cleavage from the prohormone within the A cells of the pancreatic islets but in the intestine remains as part of a partially processed precursor (glicentin). To determine whether additional glucagon-like peptides are processed from preproglucagon and to analyze for potential cellular specificity in the processing of preproglucagon, we introduced and expressed a metallothionein-glucagon fusion gene in a fibroblast and two endocrine (pituitary and pancreatic islet) cell lines. Chromatographic analyses of cell extracts utilizing specific radioimmunoassays to chemically synthesized peptides demonstrate the liberation of intact glucagon, glicentin, GLP-I(1-37), GLP-I(7-37), GLP-II, and an intervening peptide amidated at its carboxyl terminus. The peptides were present in distinct yet different patterns in the two endocrine but not the fibroblast cell lines. The cell-specific liberation of the glucagon-like and intervening peptides suggests their potential as new bioactive peptides. The cellular specificity in the processing of preproglucagon indicates that the genetic determinants of the processing activity are complex and are expressed in a cell-specific manner.

Amino Acid Sequence↗

PubMed1988

Processing-independent radioimmunoanalysis: a general analytical principle applied to progastrin and its products.

Most peptide hormone assays measure only fully processed bioactive peptides. Such assays are unsuited to detect hormone gene expression by alternative or attenuated prohormone processing (tissue- or cell-specific processing). The gastrin system is expressed in several different tissues and is therefore useful for studies of tissue-specific processing. Consequently we have developed a simple processing-independent radioimmunoanalysis for progastrin. Using antisera against the NH2-terminus of a sequence, devoid of processing sites (preprogastrin76-86) after trypsination of neighboring cleavage sites, the assay quantitates the mRNA product irrespective of degree of processing. Used together with a conventional assay for the mature carboxyamidated gastrins, the processing-independent analysis shows that in different tissues only 1 to 55% of the total translation product is processed to bioactive gastrins. Thus processing-independent analysis greatly improves the detection of gastrin gene expression at the peptide level. The principle of the assay should be applicable to all protein and peptide systems.

Amino Acid Sequence↗

PubMed1993

Modification of phospholipid membrane structure by the plant toxic peptide Pyrularia thionin.

Pyrularia thionin (P thionin) is a bioactive peptide from the parasitic plant Pyrularia pubera. The structural aspects of its interaction with phospholipid membranes were investigated by measuring the responses of phosphorescence quenching, EPR spin labels, and 1H and 31P NMR at different phospholipid compositions. In phosphatidylcholine bilayers containing cardiolipin or phosphatidylinositol, P thionin induced a pronounced increase in the membrane viscosity, and at higher P thionin concentrations the formation of nonbilayer structures was observed. In phosphatidylcholine bilayers containing phosphatidylserine, P thionin induced a significant transformation of membrane lamellar structure accompanied by a decrease of membrane viscosity. In all investigated lipid systems added P thionin caused an increase in membrane permeability and induced a fusion of sonicated liposomes. The specificity of P thionin interaction with phosphatidylserine-containing membrane is discussed and a model of phospholipid membrane modification by P thionin is suggested.

Antimicrobial Cationic Peptides↗

PubMed2004

Bioavailability of angiotensin I converting enzyme inhibitory peptides.

Hypertension or high blood pressure is a significant health problem worldwide. Bioactive peptides that inhibit angiotensin I converting enzyme (ACE) in the cardiovascular system can contribute to the prevention and treatment of hypertension. These ACE inhibitory peptides are derived from many food proteins, especially milk proteins. An ACE inhibitory activity in vitro does not always imply an antihypertensive effect in vivo. Even if it does, it is very difficult to establish a direct relationship between in vitro and in vivo activity. This is mainly due to the bioavailability of the ACE inhibitory peptides after oral administration and the fact that peptides may influence blood pressure by mechanisms other than ACE inhibition. To exert an antihypertensive effect after oral ingestion, ACE inhibitory peptides have to reach the cardiovascular system in an active form. Therefore, they need to remain active during digestion by human proteases and be transported through the intestinal wall into the blood. The bioavailability of some ACE inhibitory peptides has been studied. It is also known that (hydroxy)proline-containing peptides are generally resistant to degradation by digestive enzymes. Peptides can be absorbed intact through the intestine by paracellular and transcellular routes, but the potency of the bioactivity after absorption is inversely correlated to chain length. In addition, some strategies are proposed to increase the bioavailability of ACE inhibitory peptides. Further research into the bioavailability of ACE inhibitory peptides will lead to the development of more effective ACE inhibitory peptides and foods.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Antihypertensive peptides derived from food proteins.

This paper reviews the angiotensin I converting enzyme inhibitory peptides originated from food materials and enzymatic hydrolysate of different kinds of proteins. Focus was put on the peptides derived from milk casein by the action of the proteolytic system of lactic acid bacteria. Some of the peptides exhibit significant antihypertensive effects in spontaneously hypertensive rats. Some new topics relating to these antihypertensive peptides are introduced. The possible significance of bioactive peptides derived from food in vivo is also discussed.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Isolation and characterization of four VIP-related peptides from red-bellied newt, Cynops pyrrhogaster.

Four novel bioactive peptides were isolated from the red-bellied newt, Cynops pyrrhogaster, using a bioassay system monitoring the rectum contraction of the Japanese quail, Coturnix japonica. As these peptides are structurally related to vasoactive intestinal polypeptide (VIP), we termed these peptides newt VIP-related peptides 1, 2, 3, and 4 (NVRP-1, -2, -3, and -4). The primary sequences of these peptides were determined to be HSDAVFTDNYSRLLGKTALKNYLDGALKKE (NVRP-1), HSDAVFTDNYSRLLAKTALKNYLDGALKKE (NVRP-2), HSDAVFT-DNYSRLLGKIALKNYLDEALKKE (NVRP-3), and HSDAVFTDNYSRLLGKT-ALKNYLDSALKKE (NVRP-4). The N-terminal regions of these NVRPs possessed homology at the amino-acid level to various VIP, while the NVRP C-termini differed from VIPs significantly. All of the VIP consist of 28 amino-acid residues with amidated forms at the C-termini, whereas NVRPs possess 30 amino-acid residues and have free forms at the C-termini. NVRPs exert relaxant activities on isolated quail rectums in a dose-dependent manner, with threshold concentrations between 1 x 10(-8) and 3 x 10(-8) M. NVRPs also exhibited potent relaxant activities acting on the newt duodenum at 3 x 10(-8) M. As yet, this is the first isolation of biologically active VIP-related peptides from urodele.

Amino Acid Sequence↗

PubMed2001

Rubiscolin, a delta selective opioid peptide derived from plant Rubisco.

We found that the sequences YPLDL and YPLDLF in the large subunit of spinach D-ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) met the structure YP-aliphatic amino acid which might have opioid activity. We then synthesized these peptides to test their opioid activity. The IC(50) of these peptides in mouse vas deferens assay were 51.0 microM and 24.4 microM, respectively, and those in delta receptor binding assay using [(3)H]deltorphin II as radioligand were 2.09 microM and 0.93 microM, respectively. Both peptides were selective for delta receptor. We named them rubiscolin-5 and -6, respectively. Rubiscolin-5 and -6 have antinociceptive activity in mice after i.c.v. or oral administration. The enzymatic conditions to release rubiscolin were investigated using both spinach Rubisco and synthetic fragment peptides. This is the first example of bioactive peptides derived from plant Rubisco.

Analgesics↗

PubMed1998

Transient up-regulation of a prolyl endopeptidase activity in the microsomal fraction of rat liver during postnatal development.

To identify proteases which are involved in cell proliferation and differentiation of liver cells, we assayed various protease activities in rat liver during its postnatal development. We found that a protease activity specific to proline residues in the microsomal fraction of rat liver was transiently increased around postnatal day 8 and decreased thereafter, indicating that the enzyme activity is highly correlated to the proliferation and differentiation of liver cells. This protease was purified to an apparent homogeneity from the microsomal fraction of the postnatal-day-8 rat liver. The purified enzyme gave a single band with an apparent molecular mass of 65,000 on SDS/PAGE. It cleaved several peptide 4-methylcoumaryl-7-amide substrates and bioactive peptides at the C-terminus of proline residues. The enzyme did not hydrolyze any protein substrate examined suggesting that it is a peptidase rather than a proteinase. Although the best substrate among those tested was succinyl-Gly-Pro-Leu-Gly-Pro-4-methylcoumaryl-7-amide (-NH-Mec), the purified enzyme did not hydrolyze succinyl-Gly-Pro-NH-Mec, indicating that the enzyme has different substrate specificity from any hitherto known prolyl endopeptidases. These results suggest that the purified enzyme is a unique prolyl endopeptidase which may be involved in proliferation and differentiation of liver cells.

Animals↗

PubMed1996

Synthesis of novel (N-farnesyl) amino acids and their incorporation into peptides.

N-Alkylation, and particularly N-farnesylation, of bioactive peptides might be of wide interest: first, to increase peptide bioavailability by decreasing their elimination and by favouring their transport through biological membranes; second, to target peptides to cellular membranes; and third, to generate therapeutic double-substrate inhibitors of enzymes such as ras-farnesyltransferase. We report the synthesis of novel N-farnesyl amino acids [(N-Frn) amino acids]. We have synthesized (N-Frn)MetOCH3, (N-Frn)ValOBz and (N-Frn)PheOCH3 by alkylation of the corresponding natural amino acid esters. In order to demonstrate the feasibility of the introduction of (N-Frn) amino acids into peptides, we have synthesized representative dipeptide analogs: Cys-(N-Frn)ValOBz, Phe-(N-Frn)ValOBz, Lys-(N-Frn)ValOBz, Phe-(N-Frn)MetOCH3, Glu-(N-Frn)Me OCH3, Ser-(N-Frn)MetOCH3, Trp-(N-Frn)PheOCH3 and Pro-(N-Frn)PheOCH3. We also describe the synthesis of the model peptide Cys-Val-Phe-(N-Frn)MetOCH3, which is derived from the tetrapeptide CysValPheMet inhibitor of human p21ras-farnesyl transferase.

Amino Acids↗