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PubMed2002

Essential features of the catalytic core of peptidyl-alpha-hydroxyglycine alpha-amidating lyase.

Bioactive peptides frequently terminate with an essential alpha-amide that is generated from a COOH-terminal Gly in a two-step enzymatic process occurring within the lumen of the secretory pathway. The first enzyme, peptidylglycine alpha-hydroxylating monooxygenase, is a member of the copper- and ascorbate-dependent monooxygenase family. The second enzyme, peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL, EC 4.3.2.5), has no known homologues. Examination of the catalytic core of PAL (PALcc) using trypsin, BNPS skatole, and COOH-terminally truncated proteins failed to identify stable subdomains. Treatment of PALcc with divalent metal ion chelators inactivated the enzyme and increased its protease and thermal sensitivity, suggesting a structural role for bound metal. Purified PALcc contained 0.7 +/- 0.4 mol of zinc/mol of enzyme. Since the four Cys residues in PALcc form two disulfide bonds, potential Zn ligands include conserved Asp, Glu, and His residues. The secretion and activity of PALcc bearing mutations in each conserved Asp, Glu, and His residue were evaluated. Mutation of three conserved Asp residues and two conserved His residues yielded a protein that could not be secreted, suggesting that these residues play a structural role. Analysis of mutants that were efficiently secreted identified three His residues along with single Asp residue that may play a role in catalysis. These essential residues occur in a pattern unique to PAL.

Amidine-Lyases↗

PubMed2004

Hydrophobic core around tyrosine for human endothelin-1 investigated by photochemically induced dynamic nuclear polarization nuclear magnetic resonance and matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

Human endothelin-1 (ET-1) is a potent cardiovascular bioactive peptide. Its activity is based on the C-terminal residues, e.g., Trp 21 in particular. Recently, we reported an NMR solution structure of ET-1, which has a C-terminal hydrophobic core around Tyr 13. This C-terminal conformation does not agree with a previously reported X-ray crystal structure. To clarify the discrepancy, we performed photo-CIDNP NMR in combination with MALDI-TOF MS. The photo-CIDNP results revealed that the Tyr 13 aromatic ring is concealed in a hydrophobic interaction. MALDI-TOF MS experiments showed this is an intramolecular interaction in monomeric form, which is also supported by sedimentation analysis and two-dimensional NMR cross-peak line shapes. Thus, we confirmed the intramolecular hydrophobic core around Tyr 13 in aqueous solution, which agrees with the solution structure. The C-terminal conformational discrepancy between the solution and crystal was caused by the intermolecular hydrogen bond between Tyr 13 of one molecule and Asp 8 of the other in a dimer-like formation of crystalline ET-1. On the other hand, we indicated that endothelin-3, another isoform of the endothelin, has an apparent self-association equilibrium under the same condition in which three tyrosines participate.

Amino Acid Sequence↗

PubMed2005

Identification of casein phosphopeptides released after simulated digestion of milk-based infant formulas.

Adapted, follow-up, probiotic follow-up, toddler, and probiotic toddler infant formulas were subjected to an in vitro enzymatic procedure simulating physiological digestion. The formation and identification of casein phosphopeptides (CPPs) in the milk-based infant formulas were studied using reversed phase high-performance liquid chromatography coupled on line to an ion trap mass spectrometer. Most CPPs formed contained the cluster sequence SpSpSpEE, a mineral binding site. Phosphopeptide alpha(s2)-CN(1-19)4P was present in all formulas analyzed. Probiotic formulas released CPPs not detected in nonprobiotic formulas and probably formed by bifidobacteria action. These observations suggest that physiological digestion of these products promotes the formation of bioactive peptides with mineral carrier properties in the gastrointestinal tract, which resist further proteolysis.

Animals↗

PubMed2001

Synthesis by chemoselective ligation and biological evaluation of novel cell-permeable PKC-zeta pseudosubstrate lipopeptides.

The ability of lipopeptides to passively cross the cell membrane opens new opportunities for the intracellular delivery of bioactive peptides. However, the production of large series of cell-permeable lipopeptides is not trivial due to their generally low solubility. We have evaluated the possibility of associating the fatty acid to the functional cargo using generally applicable ligation chemistries. To this end, we have designed an amphiphilic shuttle in which arginine residues served to solubilize the lipid part in aqueous media, during both the assembly of the lipopeptide and the cellular assays. Our model peptide, the pseudosubstrate sequence of protein kinase C-zeta (PKC-zeta), was associated to the pentapeptide Gly-Arg-Gly-Arg-Lys(Pam)-NH2 through thiazolidine, thioether, disulfide, or hydrazone linkages. The cytoplasm import of the resulting constructs was monitored through the quantification of the apoptosis specifically induced by PKC-zeta inhibition. Our observations suggested the interest of this noninvasive cellular import method to modulate the activity of an intracytoplasmic pharmacological target and showed the influence of a non-amide link created between the functional peptide and the lipidic vector: optimal results, in terms of both specific activity and low basal cytotoxicity, were obtained with the thiazolidine ligation product.

Apoptosis↗

PubMed1992

N-methylated analogs of Ac[Nle28,31]CCK(26-33): synthesis, activity, and receptor selectivity.

A series of singularly N-methylated analogs of Ac[Nle28,31]CCK(26-33) were synthesized by the solid-phase methodology, and their biological activity was tested in three different in vitro bioassays. The bioassays employed were the guinea pig gallbladder (GPGB), stomach (GPS), and ileum (GPI). All N-methyl analogs were agonists in all three bioassays. N-Methylation at either N- or C-terminals did not affect potency and selectivity, whereas N-methylation of internal residues [Nle28,(N-Me)Nle31]- and [Nle28,31,(N-Me)Trp30]CCK(26-33) in the sequence resulted in analogs which were 10-fold less potent than Ac[Nle28,31]CCK(26-33) in all three preparations. Different rank orders of potencies observed for [Nle28,31,Sar29]- and [Nle28,31,(N-Me)Asp32]CCK(26-33) analogs correspond to increased selectivity to either GPGB or GPS, respectively. We propose that systematic N-methylation of single amide bonds in a bioactive peptide should be conducted as an additional routine to probe structure-activity relationships.

Amino Acid Sequence↗

PubMed1999

Corticotropin releasing factor (CRF) agonists with reduced amide bonds and Ser7 substitutions.

Strategies to generate competitive antagonists of bioactive peptides include several possible structural modifications such as the introduction of D-residues and of reduced amide bonds, the substitution of amino acid side chains, dimerization of fragments, and deletion of part of the sequence, among others. Whereas we have identified the two most likely residues responsible for receptor activation in corticotropin releasing factor (CRF) (Ser7 and Leu8)1 and generated potent antagonists by deleting residues 1-8,2,3 the question remained as to whether we could generate CRF antagonists with enhanced affinity after reduction of amide bonds at the N-terminus of CRF or through subtle alteration of those residues' side chains. Reduced amide bond replacements (psi[CH2NH]) between residues 6-9 in oCRF(5-41) (11, 12, 15) analogues consistently yielded potencies of <1% that of oCRF. Except for the 10psi11 and 12psi13 analogues 19 and 20, reduced amide bond replacements were generally well-tolerated in the longer hCRF(4-41) analogues, with the 7psi8-, 8psi9-, and 9psi10-modified peptides (13, 14, 18) yielding potencies that were 2-4 times that of hCRF. Although somewhat promising as agonists, they were, however, 3-7 times less potent than the parent [D-Pro4Nle21,38]-hCRF(4-41) (2). Since O-alkylation of Tyr3 in vasopressin yields an antagonist, and since Ser7 is one of the eight fully conserved residues in the CRF family (inclusive of sauvagine, urocortins, and urotensins) and likely to be critical for receptor binding, we synthesized cyclo(30-33)[Ser(OMe)7,D-Phe12,Nle21,Glu30,Lys33 ,Nle38]Ac-hCRF(7-41) (22), which was found to exhibit full efficacy and 40% of the potency of cyclo(30-33)[D-Phe12,Nle21,Glu30,Lys33, Nle38]Ac-hCRF(7-41) (5). Other substitutions at position 7 included aminoglycine (23, 24) and alkylated and/or acylated [alpha or alpha'-methyl (25-28), alpha'-formyl (29, 30), alpha'-formyl, alpha'-methyl (31), alpha'-acetyl (32), alpha'-acetyl, alpha'-methyl (33)], D- or L-aminoglycines. All analogues were active although less potent than the parent compound 2, and all elicited maximal ACTH response as compared to hCRF. The most potent analogue in this series (33) had the bulkiest side chain, Agl(Me, Ac), and was 60% and 80% as potent as the Ser7 analogue 5 and the Ala7 analogue 6, respectively. In conclusion, we found that neither reduction of the individual amide linkages between residues 6-11 and 12-13 nor introduction of a carbamide moiety in lieu of the side chain of Ser7 led to CRF antagonists.

Adrenocorticotropic Hormone↗

PubMed2002

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres by organocopper reagents and application to conformationally restricted cyclic RGD peptidomimetics.

Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres corresponding to dipeptides having one N-methylamino acid, and application to bioactive peptides, are described. In a key reaction introducing the chiral alpha-alkyl group of the isosteres, organocopper-mediated alkylation of syn-beta-methylated gamma-mesyloxy-alpha,beta-enoate 26a afforded E- and Z-isomers of anti-S(N)2' products in a solvent-dependent manner. The resulting two isosteres, D-Phe-psi[(E)-CH=CMe]-L-Val 27a and D-Phe-psi[(Z)-CH=CMe]-L-Val 28b, which corresponded to trans- and cis-conformers of D-Phe-L-MeVal, respectively, were utilized in a structure-activity relationship study on cyclic RGD peptides 1 and 2, in company with a psi[(E)-CH=CH]-type alkene dipeptide isostere, D-Phe-psi[(E)-CH=CH]-L-Val. The cyclic isostere-containing pseudopeptides 3, 4, and 40 were synthesized and biological activity against integrin alpha(V)beta(3) and alpha(IIb)beta(3) receptors were also evaluated.

Alkenes↗

PubMed1997

Synthesis of a Trisubstituted 1,4-Diazepin-3-one-Based Dipeptidomimetic as a Novel Molecular Scaffold.

We describe two routes for the synthesis of a trisubstituted 1,2,5-hexahydro-3-oxo-1H-1,4-diazepine ring (DAP), a novel, conformationally constrained, seven-membered dipeptidomimetic ring system. The linear precursor for the model DAPs, targeted for conformational analysis studies, was obtained by reductive alkylation of tert-butyl alaninate or phenylalaninate by N-Boc-alpha-amino-gamma-oxo-N,N-dimethylbutyramide. Acetylation of the newly formed secondary amine followed by acidolytic deprotection of the amino and carboxyl terminal protecting groups and subsequent diphenylphosphorazidate-mediated ring formation yielded the blocked model DAPs. The synthesis of the DAP synthon started with 1-tert-butyl hydrogen N-(benzyloxycarbonyl)aspartate. The aldehyde obtained from the beta-carboxyl was used to reductively alkylate benzyl phenylalaninate, generating a secondary amine. Hydrogenolytic deprotection of the end-groups yielded the linear precursor which was cyclized via lactam formation mediated by 1-hydroxy-7-azabenzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate. This route yielded the reversibly protected hexahydro-1H-3-oxo-2(S)-benzyl-5(S)-(tert-butyloxycarbonyl)-1,4-diazepine. This synthon unit can be subsequently elaborated by substituting the functional groups (secondary amine and carboxyl). Therefore, the DAPs may serve as novel molecular scaffolds to reproduce a biologically relevant topology or as a dipeptido-conformation-mimetic that can be incorporated into bioactive peptides. In addition, these synthetic routes will allow the introduction of different chiralities at positions 2 and 5 as well as the diversification of the side chains at position 2. Furthermore, the synthetic routes described here can be easily modified to obtain larger ring systems with variable degrees of conformational flexibility.

Journal Article↗

PubMed2005

Alpha-trialkylsilyl amino acid stability.

Alpha-trialkylsilyl amino acids have been evaluated for their stability toward methanolysis as a model for physiological conditions. The juxtaposition of amine and carbonyl groups significantly destabilizes the silicon-carbon bond, but changing a single methyl on silicon to an ethyl led to a dramatic stability enhancement. Converting the ester to an amide gave an additional jump in stability, suggesting broad potential for these novel amino acids in bioactive peptides and pharmaceuticals. [structure: see text]

Alkylation↗

PubMed2004

Synthesis of a Val-Pro diaminodiol dipeptide isostere by epoxyamine cyclization.

[reaction: see text] The stereoselective synthesis of a novel proline-containing dipeptide isostere is described. Starting from l-valine, three new contiguous stereocenters are generated by asymmetric induction and epoxide chemistry, while the pyrrolidine ring of proline is introduced in the final step via intramolecular ring opening of the amino acid derived epoxyamine. Proline-containing peptidomimetics are potentially attractive as selective inhibitors of proline-specific enzymes, such as PPIases and retroviral proteases, and as analogues of bioactive peptides.

Journal Article↗

PubMed2000

Preparation of biodegradable insulin nanocapsules from biocompatible microemulsions.

PURPOSE: To prepare poly(ethyl 2-cyanoacrylate) nanocapsules containing insulin by interfacial polymerization of spontaneously forming, biocompatible microemulsions. METHODS: A pseudo-ternary phase diagram of a mixture of medium chain glycerides (caprylic/capric triglycerides and mono-/diglycerides), a mixture of surfactants (polysorbate 80 and sorbitan mono-oleate) and water was constructed. Polarizing light microscopy was used to identify combinations forming microemulsions. Microemulsions were characterized by conductivity and viscosity to select systems suitable for the preparation of poly(ethyl 2-cyanoacrylate) nanocapsules by interfacial polymerization. Nanocapsules were prepared by addition of 100 mg of ethyl 2-cyanoacrylate to a stirred water-in-oil microemulsion containing 1 g of water, 7.6 g of oil, and 1.4 g of surfactant. The nanocapsules formed were characterized by photon correlation spectroscopy, freeze fracture transmission and scanning electron microscopy. Insulin nanocapsules were prepared by using an aqueous solution of insulin (100 units/ml) as the dispersed phase of the microemulsion. The entrapment and the release of insulin from the nanocapsules were determined. RESULTS: Three regions were identified in the pseudo-ternary phase diagram; a microemulsion region, a region in which liquid crystalline structures were present and a coarse emulsion region. All systems in the microemulsion region were water-in-oil dispersions. Poly(ethyl 2-cyanoacrylate) nanocapsules having a mean particle size of 150.9 nm were formed upon interfacial polymerization of the microemulsion. Nanocapsules were found to have a central cavity surrounded by a polymer wall. In excess of 80% of the insulin present in the microemulsion was encapsulated upon interfacial polymerization. CONCLUSIONS: Interfacial polymerization of spontaneously forming water-in-oil microemulsions represents a convenient method for the preparation of poly(alkylcyanoacrylate) nanocapsules suitable for the entrapment of bioactive peptides.

Absorbable Implants↗

PubMed2000

Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis.

We report here the molecular cloning of a newly identified preprotachykinin gene, Pptc, which specifies the sequence for a new preprotachykinin protein and bioactive peptide designated hemokinin 1 (HK-1). PPT-C mRNA was detected primarily in hematopoietic cells in contrast to the previously described Ppta and Pptb genes, which are predominantly expressed in neuronal tissues. HK-1 has several biological activities that are similar to the most studied tachykinin, substance P, such as induction of plasma extravasation and mast cell degranulation. However, HK-1 also has properties that are indicative of a critical role in mouse B cell development. HK-1 stimulated the proliferation of interleukin 7-expanded B cell precursors, whereas substance P had no effect. HK-1, but not substance P, promoted the survival of freshly isolated bone marrow B lineage cells or cultured, lipopolysaccharide-stimulated pre-B cells. N-acetyl-L-trytophan-3,5-bistrifluromethyl benzyl ester, a tachykinin receptor antagonist, increased apoptosis of these cells and in vivo administration of this antagonist led to specific reductions of the B220lowCD43 population (the pre-B cell compartment) in the bone marrow and the IgMhighIgDlow population (the newly generated B cells) in the spleen. Thus, HK-1 may be an autocrine factor that is important for the survival of B cell precursors at a critical phase of development.

Amino Acid Sequence↗

PubMed1989

Analysis of the complement C3 fragments associated with hemodialysis membranes.

During hemodialysis with cuprophan membranes, bioactive peptides are generated because the alternative pathway of complement is activated. When cellulose acetate membranes are employed, complement activation is attenuated. The molecular basis for this improved biocompatibility is unknown. It has been postulated, however, that the complement activating potential of dialysis membranes is influenced by the availability of free hydroxyl groups which would provide an acceptor site for activated C3. To investigate this hypothesis, the forms of C3 associated with cellulose acetate and cuprophan membranes have been analyzed. By Western blot, the predominant form of C3 present on both types of membranes is C3c, a degradation product of C3 that lacks the thiolester necessary for covalent bonding. Minimal amounts of C3d (the region of C3 which contains the thiolester) were observed on both membranes; however, by ELISA, there was no difference in the amount bound to cellulose acetate compared to cuprophan. Further, membrane-associated C3d could be removed by urea, suggesting that it was not bound covalently. These studies indicate that the complement activating potential of dialysis membranes is not determined primarily by the availability of potential covalent binding sites for activated C3b.

Blotting, Western↗

PubMed2004

Regulation of aminopeptidase A expression in cervical carcinoma: role of tumor-stromal interaction and vascular endothelial growth factor.

We previously demonstrated that aminopeptidase A (APA), a membrane-bound metallopeptidase degrading bioactive peptides such as angiotensin II (Ang II), is expressed in neoplastic lesions of the uterine cervix, and that its expression is upregulated as the lesion progresses from cervical intraepithelial neoplasms (CIN) toward invasive squamous cell carcinomas (SCC). The present study investigated the regulatory mechanisms involved in APA expression and its potential role in cervical carcinoma. Immunohistochemical staining in high-grade CIN and SCC tissues showed that APA was strongly expressed at the edge of lesions adjacent to cervical stromal cells. Fluorescence-activated cell sorting analysis demonstrated that cell surface APA expression was extremely low in three human SCC cell lines, SiHa, TCS and CaSki, under basal conditions. However, both contact and noncontact cocultures with human cervical fibroblasts resulted in the induction of APA expression in these SCC cells. APA expression was also induced in vivo when TCS cells were subcutaneously inoculated into nude mice. Furthermore, APA expression and enzymatic activity were enhanced by addition of the conditioned medium (CM) from fibroblast culture, but not by heat-treated CM. Among the various cytokines tested, vascular endothelial growth factor (VEGF) significantly increased APA activity, and induction of APA by the fibroblast CM was partly inhibited by anti-VEGF neutralizing antibody. Finally, APA cDNA-transfected APA-overexpressing TCS cells significantly reduced the Ang II-induced cell invasion ability as compared with parental or control vector-transfected TCS cells, although there was no significant difference in cellular proliferation among them. These results suggested the importance of tumor-stromal interaction for the regulation of APA expression in the microenvironment of cervical carcinoma and the potential role for this peptidase in regulating tumor invasion through inactivation of Ang II activity.

Angiotensin II↗

PubMed2000

The expression and localization of neutral endopeptidase 24.11/CD10 in human gestational trophoblastic diseases.

Neutral endopeptidase 24.11 (NEP)/CD10 is a cell-surface peptidase that hydrolyzes various bioactive peptides. NEP is distributed in both normal and neoplastic cells and plays a functional role by modulating cellular responses to peptide substrates. Recently, NEP has been shown to be expressed in normal placental trophoblasts, suggesting its physiological role during pregnancy. In the present study, we investigated the expression of NEP in hyperplastic and anaplastic trophoblasts in gestational trophoblastic diseases (GTDs). Flow cytometric analysis demonstrated that NEP was expressed in all choriocarcinoma cell lines examined. The NEP enzyme activity in these cell lines correlated with cell-surface protein levels and was abolished by the NEP inhibitor phosphoramidon. On immunoblot analysis, NEP protein was detected in both hydatidiform mole and choriocarcinoma tissues as a double band of 95 and 100 kDa similar to that of the normal placental tissues. Immunohistochemical analysis revealed that NEP was present on syncytiotrophoblasts, while no or very faint NEP immunoreactivity was observed on cytotrophoblasts in the normal placenta. Similarly, NEP in hydatidiform mole and invasive mole was localized on the membrane of syncytiotrophoblasts, but not on hyperplastic cytotrophoblasts. In contrast, in choriocarcinoma, NEP was highly expressed not only on syncytiotrophoblastic cells but also on invading anaplastic cytotrophoblasts. In addition, NEP was also expressed on intermediate trophoblasts in placental site trophoblastic tumors. In summary, this is the first study demonstrating the expression of NEP/CD10 in GTDs. The differential localization of NEP among various trophoblastic tumors suggests that NEP may play a functional role in the regulation of trophoblast transformation and human chorionic gonadotropin secretion.

Blotting, Western↗

PubMed2006

Stromal CD10 expression in invasive breast carcinoma correlates with poor prognosis, estrogen receptor negativity, and high grade.

CD10 is a zinc-dependent peptidase (metalloproteinase), which degrades a variety of bioactive peptides. Earlier studies suggested that CD10 expression in tumor stroma is associated with biological aggressiveness of the tumor. To date, only one study has addressed the clinical significance of stromal CD10 expression in invasive carcinoma of the breast. The aim of this confirmatory study is to evaluate stromal CD10 expression in breast carcinoma and to examine associations between CD10, clinicopathological variables, and patient outcome. Tissue microarrays, containing 438 cases of invasive breast carcinoma and 15 cases of ductal carcinoma in situ with 15 years median follow-up time, were assembled. CD10 expression was assessed by immunohistochemistry and scored as negative, weak and strong. Nonparametric correlational tests, univariate and multivariate survival analyses were performed. Stromal CD10 was preferentially expressed in invasive compared to noninvasive breast cancers (P=0.003). There were correlations between stromal CD10 expression and higher tumor grade (P=0.01) and estrogen receptor (ER) negative status (P=0.002). There was no correlation between CD10 and lymph node status, tumor size, histological subtype, progesterone receptors, and Her2 status. Stromal CD 10 expression was associated with decreased long-term disease-specific and overall survival in the entire cohort (P<0.01), and in lymph node negative (P<0.05), but not lymph node positive subset of patients. It approached prognostic significance in multivariate analysis (P=0.06) when lymph node status, tumor size, ER and Her2 were considered in the same model; and was associated with a relative risk of death of 2.8, compared to relative risk of 2.4 for lymph node positive status. Thus, stromal CD10 expression in invasive carcinoma of the breast is associated with ER negativity, higher tumor grade and decreased survival and constitutes a potential prognostic marker and a target for development of novel therapies.

Adult↗

PubMed2000

Immunohistochemical expression of chromogranins A and B, prohormone convertases 2 and 3, and amidating enzyme in carcinoid tumors and pancreatic endocrine tumors.

Although chromogranin A (CgA) is widely distributed in neuroendocrine tumors, the distribution of chromogranin B (CgB) has not been elucidated. Hormones produced by tumors are sometimes prohormones and not necessarily bioactive hormones. Prohormones have to be processed into bioactive peptides by prohormone convertases (PCs), and some of them have to be amidated by peptidylglycine a-amidating monooxygenase (PGM). Whether PCs and PGM are present or not in tumors may explain why some tumors are functioning and some are nonfunctioning. We investigated 45 carcinoids and 16 pancreatic endocrine tumors. Of the carcinoids, CgA was expressed in most of the tumors, except for the rectal and ovarian carcinoids, which expressed CgB strongly. The expressions of PC2, PC3, and PGM were 31%, 100%, and 87%, respectively. In the pancreatic tumors, CgA was expressed in all tumors, whereas CgB was not expressed in any tumor. The expressions of PC2, PC3, and PGM were 63%, 88%, and 63%, respectively. PC3 was expressed in all of the functioning tumors but not in two of the four nonfunctioning tumors. PC2 and PGM were not expressed in three of the four nonfunctioning tumors. In conclusion, expression of CgA and CgB was different depending on the tumor location. High frequency of PCs and PGM may explain why even nonfunctioning tumors produce some inconspicuous peptides.

Adenoma, Islet Cell↗

PubMed1998

Production of biologically active salmon calcitonin in the milk of transgenic rabbits.

Salmon calcitonin (sCT) is an example of one of the many bioactive peptides that require amidation of the carboxy terminus for full potency. We describe a method for the production of amidated sCT in the mammary gland of transgenic rabbits. Expression of a fusion protein comprising human alpha lactalbumin joined by an enterokinase cleavable linker to sCT was directed to the mammary gland under the control of the ovine beta lactoglobulin promoter. C-terminal amidation in vivo was achieved by extending the sCT by a single glycine residue that provides a substrate for endogenous amidating activity in the mammary gland. Full characterization of the released sCT demonstrated it to be equivalent to synthetic standard in terms of structure, purity, and potency.

Amides↗