Calcitonin Analogue Research Articles

Physiological and Therapeutic Role of Calcitonin

Homosapeins have been identified with over 50 hormones. Hormones control or regulate different biological processes. Among all, Calcitonin is one of theabandoned hormones. Calcitonin is released from the C-cell of the thyroid gland. Thyrocalcitonin is a type of neuroendocrine composed of 32 amino acids released from parafollicular cells(C-Cells) present in the thyroid gland in human beings and many other animals in the body. The utility of hormones is still under consideration. Calcitonin is physiologically involved in the maintenance of the calcium and phosphate levels in the blood. As diagnostic parameter utility is observed in the diagnosis of medullary thyroid cancer, C cell hyperplasia. Therapeutically the monoclonal antibodies derived from calcitonin are effective for the treatment of migraine. It possesses anodynic, cardioprotective, and peripheral nerve regeneration. Recent research shows the use of human analogue calcitonin as FDA approved second-line treatment for Paget’s disease. Calcitonin analogue shows its usefulness, especially in the case of bisphosphate tolerance. Calcitonin will be a research topic for future perspective. This study was conducted to the elaborate role of calcitonin in human physiologyThis study involved the utilization of standard databases like PubMed and google scholar to determine the different roles of calcitonin in pathological and physiologicalThe present study shows that calcitonin levels are not only raised in diagnosing C -cell hyperplasia and medullary thyroid cancer, but other conditions are responsible for increased calcitonin in the systemic circulation.The current study manifests the role of calcitonin as a diagnostic parameter and pharmacological treatment. It was observed that calcitonin can be helpful in another pathological disease.

Type II Turn of Receptor-bound Salmon Calcitonin Revealed by X-ray Crystallography

Calcitonin is a peptide hormone consisting of 32 amino acid residues and the calcitonin receptor is a Class B G protein-coupled receptor (GPCR). The crystal structure of the human calcitonin receptor ectodomain (CTR ECD) in complex with a truncated analogue of salmon calcitonin ([BrPhe(22)]sCT(8-32)) has been determined to 2.1-Å resolution. Parallel analysis of a series of peptide ligands showed that the rank order of binding of the CTR ECD is identical to the rank order of binding of the full-length CTR, confirming the structural integrity and relevance of the isolated CTR ECD. The structure of the CTR ECD is similar to other Class B GPCRs and the ligand binding site is similar to the binding site of the homologous receptors for the calcitonin gene-related peptide (CGRP) and adrenomedulin (AM) recently published (Booe, J. M., Walker, C. S., Barwell, J., Kuteyi, G., Simms, J., Jamaluddin, M. A., Warner, M. L., Bill, R. M., Harris, P. W., Brimble, M. A., Poyner, D. R., Hay, D. L., and Pioszak, A. A. (2015) Mol. Cell 58, 1040-1052). Interestingly the receptor-bound structure of the ligand [BrPhe(22)]sCT(8-32) differs from the receptor-bound structure of the homologous ligands CGRP and AM. They all adopt an extended conformation followed by a C-terminal β turn, however, [BrPhe(22)]sCT(8-32) adopts a type II turn (Gly(28)-Thr(31)), whereas CGRP and AM adopt type I turns. Our results suggest that a type II turn is the preferred conformation of calcitonin, whereas a type I turn is the preferred conformation of peptides that require RAMPs; CGRP, AM, and amylin. In addition the structure provides a detailed molecular explanation and hypothesis regarding ligand binding properties of CTR and the amylin receptors.

Crystal structure of the calcitonin receptor ectodomain in complex with a truncated salmon calcitonin analogue

Crystal structure of the calcitonin receptor ectodomain in complex with a truncated salmon calcitonin analogue

Acylation of salmon calcitonin modulates in vitro intestinal peptide flux through membrane permeability enhancement

Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation, as well as increasing enzymatic stability and interactions with lipid cell membranes. Thus, acylation offers several potential benefits for oral delivery of therapeutic peptides, and we hypothesize that tailoring the acylation may be used to optimize intestinal translocation. This work aims to characterize acylated analogues of the therapeutic peptide salmon calcitonin (sCT), which lowers blood calcium, by systematically increasing acyl chain length at two positions, in order to elucidate its influence on intestinal cell translocation and membrane interaction.We find that acylation drastically increases in vitro intestinal peptide flux and confers a transient permeability enhancing effect on the cell layer. The analogues permeabilize model lipid membranes, indicating that the effect is due to a solubilization of the cell membrane, similar to transcellular oral permeation enhancers. The effect is dependent on pH, with larger effect at lower pH, and is impacted by acylation chain length and position. Compared to the unacylated peptide backbone, N-terminal acylation with a short chain provides 6- or 9-fold increase in peptide translocation at pH 7.4 and 5.5, respectively. Prolonging the chain length appears to hamper translocation, possibly due to self-association or aggregation, although the long chain acylated analogues remain superior to the unacylated peptide. For K18-acylation a short chain provides a moderate improvement, whereas medium and long chain analogues are highly efficient, with a 12-fold increase in permeability compared to the unacylated peptide backbone, on par with currently employed oral permeation enhancers. For K18-acylation the medium chain acylation appears to be optimal, as elongating the chain causes greater binding to the cell membrane but similar permeability, and we speculate that increasing the chain length further may decrease the permeability.In conclusion, acylated sCT acts as its own in vitro intestinal permeation enhancer, with reversible effects on Caco-2 cells, indicating that acylation of sCT may represent a promising tool to increase intestinal permeability without adding oral permeation enhancers.

Evaluation of bone targeting salmon calcitonin analogues in rats developing osteoporosis and adjuvant arthritis.

Synthetic analogues of the peptide hormone calcitonin have been used in medicine as biologic drug therapies for decades, to treat pathological conditions of excessive bone turnover, such as osteoporosis, where more bones are removed than replaced during bone remodeling. Osteoporosis and other chronic skeletal diseases, including inflammatory arthritis, exact a substantial and growing toll on aging populations worldwide however they respond poor to synthetic biologic drug therapy, due in part to the rapid half-life of elimination, which for calcitonin is 43 minutes. To address those shortcomings, we have developed and synthesized bone-targeting variants of calcitonin as a targeted drug delivery strategy, by conjugation to bisphosphonate drug bone-seeking functional groups in highly specific reaction conditions. To evaluate their in vivo efficacy, bisphosphonate-mediated bone targeting with PEGylated (polyethylene glycol conjugated) and non-PEGylated salmon calcitonin analogues were synthesized and dose escalation was performed in female rats developing Osteoporosis. The bone-targeting calcitonin analogues were also tested in a separate cohort of male rats developing adjuvant-induced arthritis. Ovariectomized female rats developing Osteoporosis were administered daily sub-cutaneous injection of analogues equivalent to 5, 10 and 20 IU/kg of calcitonin for 3 months. Adjuvant arthritis was developed in male rats by administering Mycobacterium butyricum through tail base injection. Daily sub-cutaneous injection of analogues equivalent to 20 IU/kg of calcitonin was administered and the rats were measured for visible signs of inflammation to a 21 day endpoint. In both studies, the effect of drug intervention upon bone volume and bone mineral density (BMD) was assessed by measuring the trabecular bone volume percentage and BMD at the proximal tibial metaphysis using in vivo micro-computed tomography. With dose escalation studies, only bone targeting analogue dosed groups showed a trend towards increased BMD and bone volume at 4, 8 and 12 weeks. Significant preservation of bone volume and BMD as evidenced by nonsignificant (P<0.05) loss of bone volume and BMD at the end of 3 month study endpoint was seen in animals dosed with 20 IU/kg of calcitonin compounds. Similarly, in case of adjuvant-induced arthritis rats, there was a significant increase (P<0.05) in bone volume and BMD in calcitonin-bisphosphonate and calcitonin-PEG-bisphosphonate treated groups at 21 days compared to the baseline values. Improved efficacy in terms of preserving bone volume and BMD in Osteoporosis, and in rats developing adjuvant-induced arthritis, by these analogues suggests their potential as new drug candidates for further evaluation to determine their usefulness in bone diseases characterized by excessive bone resorption.

THU0205 Targeting the Bone-Driven Phenotype of OA by A Novel Calcitonin Analogue, Kbp088, Affecting Both Bone and Cartilage Turnover as Well as Metabolic Health

BackgroundOsteoarthritis (OA) may be segregated into different disease phenotypes based on disease drivers; cartilage damage, joint inflammation or subchondral bone remodelling. Each phenotype may require targeted treatments. Patients with a...

Comparison of the Effects of Single Doses of Elcatonin and Pregabalin on Oxaliplatin-Induced Cold and Mechanical Allodynia in Rats

Oxaliplatin frequently causes peripheral neuropathy. Clinical studies have indicated that pregabalin ameliorates oxaliplatin-induced peripheral neuropathy. However, pregabalin frequently causes dizziness and somnolence. We previously reported that elcatonin, a synthetic analog of eel calcitonin, attenuated oxaliplatin-induced cold and mechanical allodynia in rats. The aim of the present study was to compare the anti-allodynic effects of elcatonin and pregabalin in the rats developing the oxaliplatin-induced neuropathy. Male Sprague-Dawley rats were treated with a single dose of oxaliplatin (6 mg/kg, intraperitoneally (i.p.)) to induce cold and mechanical allodynia. We assessed the effects of subcutaneous elcatonin (20 U/kg) and oral pregabalin (30 mg/kg) on cold and mechanical allodynia by cold stimulation (8°C) to the hind paw of the rats and the von Frey test, respectively. Elcatonin reversed the effects of oxaliplatin-induced cold and mechanical allodynia in rats for a longer time period than pregabalin does. These results suggested that elcatonin might be useful for the clinical treatment of oxaliplatin-induced neuropathy.

Synthesis, Characterization and Biodistribution Studies of 125I-Radioiodinated di-PEGylated Bone Targeting Salmon Calcitonin Analogue in Healthy Rats

The objective of this study was to prepare a bisphosphonate (BP) mediated bone targeting di-PEGylated salmon calcitonin analogue sCT-2(PEG-BP) as a novel bone targeting pharmaceutical. HPLC was used for isolation of sCT-2(PEG-BP) from the reaction mixture, followed by determination of possible PEGylation sites by trypsin digestion. Stability of the compound over time, bone mineral affinity using hydroxyapatite, and biodistribution in normal rats after radiolabeling of sCT-2(PEG-BP) or control sCT with (125)I was evaluated. PEGylated sCT analogues were synthesized, and sCT-2(PEG-BP) was isolated by HPLC and confirmed by MALDI-TOF and ICP-MS. MALDI-TOF analysis of trypsinized fragments suggested Cys(1) (or Lys(11)) and Lys(18) to be the two PEGylation sites. Bone mineral affinity test showed sCT-2(PEG-BP) or (125)I-sCT-2(PEG-BP) exhibited significantly increased bone mineral affinity over sCT or (125)I-sCT, respectively. sCT-2(PEG-BP) remained stable for at least 1month. In vivo biodistribution study showed significantly increased bone retention and prolonged plasma circulation time for sCT-2(PEG-BP) compared to the control sCT. Those results support sCT-2(PEG-BP) as a promising new drug candidate for the treatment of resorptive and/or maladaptive bone conditions, such as Osteoporosis, Osteoarthritis, Rheumatoid Arthritis, Paget's disease and bone cancers.

Salmon Calcitonin Reduces Oxaliplatin-Induced Cold and Mechanical Allodynia in Rats

Oxaliplatin is commonly used anti-cancer drugs, but it frequently causes peripheral neuropathic pain. Recently, we reported that elcatonin, a synthetic analog of eel calcitonin, attenuated the oxaliplatin- and paclitaxel-induced cold and mechanical allodynia in rats. In the present study, we determined whether salmon calcitonin also had anti-allodynic effects on oxaliplatin-induced neuropathy in rats. The rats were treated with a single dose of oxaliplatin (6 mg/kg, intraperitoneally (i.p.)). Oxaliplatin resulted in cold and mechanical allodynia. We assessed the anti-allodynic effects of subcutaneously administered salmon calcitonin (20 U/kg/d) by cold stimulation (8°C) directly to the hind paw of the rats and by using the von Frey test. Salmon calcitonin almost completely reversed the effects of both cold and mechanical allodynia. These results suggest that salmon calcitonin is also useful for treatment of oxaliplatin-induced neuropathy clinically.

Synthesis, characterization and evaluation of bone targeting salmon calcitonin analogs in normal and osteoporotic rats

In order to assess the therapeutic efficacy of an antiresorptive drug with imparted bone targeting potential using bisphosphonate (BP) conjugation and an improved pharmacokinetic profile using PEGylation, we synthesized, characterized and evaluated in vivo efficacy of bone-targeting PEGylated salmon calcitonin (sCT) analog (sCT-PEG-BP). sCT-PEG-BP was compared with non-PEGylated bone targeting sCT analog (sCT-BP) and unmodified, commercially available sCT. sCT-PEG-BP conjugates were characterized by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) analysis. The effect of PEG-BP or BP upon sCT secondary structure was examined by Circular Dichroism and sCT-PEG-BP was evaluated for in vitro bone mineral Hydroxyapatite (HA) binding ability and calcium salts specificity using a binding assay for bone HA and several calcium salts. Anti-calcitonin antibody binding ability of these analogs was determined using enzyme-linked immunosorbent assay (ELISA), by reacting bone targeting sCT analogs with calcium phosphate coated Osteologic® plates and detecting the bound sCT using anti-sCT antibody. Potential cytotoxicity of these compounds was evaluated in monocytic RAW 264.7 cells, and sCT bioactivity was evaluated using an in vitro intracellular cAMP stimulation assay in human T47D breast cancer cells. Finally, in vivo efficacy of each compound was evaluated by determining the plasma levels of calcium after s.c. administration in normal rats, and in a rat model of Osteoporosis, secondary to ovariectomy (OVX). In vivo micro-computed tomography (micro-CT) was used to temporally map and quantify alterations in bone volume and bone mineral density (BMD) in the same animals at 1, 4, 8 and 12weeks after OVX surgery. Sixteen 6week old virgin female rats underwent OVX surgery followed by the daily s.c. injection of 2.5IU/kg/day sCT or equivalent analogs, and compared to four sham-operated, placebo treated control rats. Our results showed the chemical coupling of PEG-BP or BP to sCT altered its secondary structure without altering its antibody binding ability. sCT analogs retained strong sCT bioactivity, were non-toxic to RAW 264.7 cells in culture and elicited a comparable hypocalcemic effect to that of unmodified sCT in normal rats. Compared to marketed unmodified sCT, sCT-PEG-BP showed significantly improved efficacy in terms of preserving bone volume, BMD and trabecular micro-architecture in osteoporotic rats at the initial dose tested. Bisphosphonate-mediated targeting of PEGylated sCT to bone represents a new class of targeted antiresorptive compounds that has not previously been attempted.

Effect of non-ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]-eel calcitonin in rats.

The effect of non-ionic surfactants in a polyacrylic acid gel base on the rectal absorption of [Asu1,7]-eel calcitonin, a calcitonin analogue, was studied in rats. Absorption was enhanced by a microenema which used a polyacrylic acid gel base, but it was reduced by the incorporation of polysorbate 80 (0.1-5% v/v). The incorporation of polyoxyethylene 9 lauryl ether (0.1-5% v/v) in the polyacrylic acid gel base enhanced the absorption. Rectal administration in the base containing 0.5% v/v polyoxyethylene 9 lauryl ether required a dose of the calcitonin 2-3 times greater than an intramuscularly administered dose to achieve an equivalent hypocalcaemic effect.

Biodegradable Poly(D,L-lactic Acids) for In-vivo Controlled Delivery of Calcitonin in Rats

Poly(D,L-lactic acids) (PLA) with number-average molecular weights (Mn) of 1400, 2000 and 4400 were synthesized by polycondensation in the presence of water, to investigate the degree of in-vivo degradation and the degradation patterns. The degree of degradation of PLA implanted subcutaneously in the back of rats was found to be approximately 100, 42, and 5%, respectively, at the third week from the start of the implantation, during which the degradation pattern was changed from parabolic-type to S-type, as the molecular weight was increased. A synthetic analogue of eel calcitonin, [Asu1,7]-ECT, was incorporated into a fine cylinder of PLA. The initial burst of drug released in-vivo from the cylindrical PLA formulation could be retarded by adjusting the molecular weight of the polymers.

Actions of β-Amyloid Protein on Human Neurons Are Expressed through the Amylin Receptor

Disruption of neurotoxic effects of amyloid β protein (Aβ) is one of the major, but as yet elusive, goals in the treatment of Alzheimer's disease (AD). The amylin receptor, activated by a pancreatic polypeptide isolated from diabetic patients, is a putative target for the actions of Aβ in the brain. Here we show that in primary cultures of human fetal neurons (HFNs), AC253, an amylin receptor antagonist, blocks electrophysiological effects of Aβ. Pharmacological blockade of the amylin receptor or its down-regulation using siRNA in HFNs confers neuroprotection against oligomeric Aβ-induced caspase-dependent and caspase-independent apoptotic cell death. In transgenic mice (TgCRND8) that overexpress amyloid precursor protein, amylin receptor is up-regulated in specific brain regions that also demonstrate an elevated amyloid burden. The expression of Aβ actions through the amylin receptor in human neurons and temporospatial interrelationship of Aβ and the amylin receptor in an in vivo model of AD together provide a persuasive rationale for this receptor as a novel therapeutic target in the treatment of AD.

Synthesis, Characterization and In Vivo Activity of Salmon Calcitonin Coconjugated With Lipid and Polyethylene Glycol

An irreversible lipidized salmon calcitonin (sCT) analog, Mal-sCT, was previously shown to have comparable hypocalcemic activity to sCT in vivo. This study reports on the synthesis, characterization and pharmacological activity of novel PEGylated Mal-sCT analogs. Mal-sCT, prepared by conjugating sCT via thio-ether bonds with aqueous-soluble palmitic acid derivative at Cys 1 and Cys 7, was reacted with mPEG-succinimide (mPEG-Suc, 5 kDa). The products were purified and then identified by MALDI-TOF MS and HPLC. Mal-sCT was conjugated with 1 (1PEG-Mal-sCT) or 2 (2PEG-Mal-sCT) PEG chains at Lys 11 and Lys 18, the former being the preferred site of conjugation at higher mPEG-Suc/Mal-sCT ratio. Circular dichroism analysis showed the PEGylated Mal-sCT analogs to possess a robust helical conformation, while size measurement by dynamic light scattering indicated a propensity of the peptides to self-aggregate in aqueous solutions. Both 1PEG-Mal-sCT and 2PEG-Mal-sCT were more stable in rodent intestinal fluids than sCT or Mal-sCT. However, 1PEG-Mal-sCT had comparable hypocalcemic activity to Mal-sCT when injected subcutaneously in the rat, while 2PEG-Mal-sCT was inactive. 1PEG-Mal-sCT was inactive when administered orally in the rat. This study suggested PEGylation of Mal-sCT increased the stability of the lipidized peptide to enzyme degradation, but did not enhance its hypocalcemic activity.

Increased Renal Calcium Reabsorption by Parathyroid Hormone–Related Protein Is a Causative Factor in the Development of Humoral Hypercalcemia of Malignancy Refractory to Osteoclastic Bone Resorption Inhibitors

Bisphosphonate and calcitonin lower blood calcium in humoral hypercalcemia of malignancy (HHM) by suppressing osteoclastic bone resorption, but repeated administration of these drugs often leads to relapse. In this study, we examined the roles of parathyroid hormone-related protein (PTHrP) in the development of bisphosphonate- and calcitonin-refractory HHM. Nude rats bearing the LC-6 JCK tumor xenograft (LC-6 rats) exhibited high bone turnover and HHM. Repeated administration of alendronate induced a sustained suppression of the bone resorption, but it caused only early and transient reduction of the blood calcium levels, leading to unresponsiveness to the drug. Because high blood levels of PTHrP were detected in the LC-6 rats, those that developed alendronate-refractory HHM were treated with an anti-PTHrP antibody. Administration of anti-PTHrP antibody to animals that received repeated administration of alendronate, thereby developing alendronate-refractory HHM, resulted in an increase in fractional excretion of calcium and a marked decrease of blood calcium level. Drug-refractory HHM was also observed in animals that received another osteoclast inhibitor, an eel calcitonin analogue elcatonin. The blood calcium level decreased after the initial administration of elcatonin, but it eventually became elevated during repeated administration. Administration of the anti-PTHrP antibody, but not of alendronate, effectively reduced the blood calcium of the animals that developed elcatonin-refractory HHM. High levels of circulating PTHrP and the resulting augmentation of renal calcium reabsorption is one of the major causes of the emergence of osteoclast inhibitor-refractory HHM. Thus, blockage of PTHrP functions by a neutralizing antibody against PTHrP would benefit patients who develop bisphosphonate- or calcitonin-refractory HHM.

Contribution of Conformationally Constrained Calcitonin (Ct) Analogs to the Understanding of the Structural and Conformational Requirements of Calcitonin Bioactivity and to the Design of Potent Agonists

Restricting the conformational flexibility of medium-sized linear polypeptides is a valuable approach to identify and characterize the structural and conformational features that define their biological activities and to design analogs with enhanced agonistic or antagonistic properties and with potential therapeutic applications. The calcium-regulating and bone resorption-inhibiting hormone calcitonin (Ct) is a conformationally flexible polypeptide of 32 amino acid residues that has long been applied therapeutically for the treatment of osteoporosis and other bone disorder diseases. This review describes studies on the structural and conformational features of the Ct sequence that are relevant for Ct bioactivity and focuses on research work performed on rationally designed conformationally constrained Ct analogs as tools for the understanding of the molecular basis of Ct bioactivity and as potential candidates or lead structures for novel Ct-based bone disorder therapeutics.

Spatial Proximity between a Photolabile Residue in Position 19 of Salmon Calcitonin and the Amino Terminus of the Human Calcitonin Receptor

Calcitonins are 32-amino acid peptide hormones with both peripheral and central actions mediated via specific cell surface receptors, which belong to the class II subfamily of G protein-coupled receptors. Understanding receptor function, particularly in terms of ligand recognition by calcitonin receptors, may aid in the rational design of calcitonin analogs with increased potency and improved selectivity. To directly identify sites of proximity between calcitonin and its receptor, we carried out photoaffinity labeling studies followed by protein digestion and mapping of the radiolabeled photoconjugated receptor. A fully active salmon calcitonin analog [Arg(11,18),Bpa19]sCT, incorporating a photolabile p-benzoyl-L-phenylalanine into position 19 of the ligand, has been used to demonstrate spatial proximity between residue 19 of the peptide and the amino-terminal extracellular domain of the receptor. Cyanogen bromide cleavage together with endoproteinase Asp-N digestion indicated that binding was predominantly to the region delimited by receptor residues Cys134 and Met187. Binding to this fragment was supported further by cyanogen bromide-digestion of receptors that were mutated to remove the predicted cleavage site at Met133 (M133A, M133L). Binding within the 54-amino acid fragment was refined further by digestion with endoproteinase Lys-C to the 8-amino acid region corresponding to Cys134-Lys141. These results provide the first direct demonstration of a contact domain between salmon calcitonin and its receptor and will contribute toward modeling of the calcitonin-receptor interface.

Importance of the Amino Terminus in Secretin Family G Protein-coupled Receptors: INTRINSIC PHOTOAFFINITY LABELING ESTABLISHES INITIAL DOCKING CONSTRAINTS FOR THE CALCITONIN RECEPTOR

The calcitonin receptor is a member of the class B family of G protein-coupled receptors, closely related to secretin and parathyroid hormone receptors. Although mechanisms of ligand binding have been directly explored for those receptors, current knowledge of the molecular basis of calcitonin binding to its receptor is based only on receptor mutagenesis. In this work we have utilized the more direct approach of photoaffinity labeling to explore spatial approximations between distinct residues within calcitonin and its receptor. For this we have developed two human calcitonin analogues incorporating a photolabile p-benzoyl-l-phenylalanine residue in the mid-region and carboxyl-terminal half of the peptide in positions 16 and 26, respectively. Both probes specifically bound to the human calcitonin receptor with high affinity and were potent stimulants of cAMP accumulation in calcitonin receptor-bearing human embryonic kidney 293 cells. They covalently labeled the calcitonin receptor in a saturable and specific manner. Further purification, deglycosylation, specific chemical and enzymatic cleavage, and sequencing of labeled wild type and mutant calcitonin receptors identified the sites of labeling for the position 16 and 26 probes as receptor residues Phe137 and Thr30, respectively. Both were within the extracellular amino terminus of the calcitonin receptor, with the former adjacent to the first transmembrane segment and the latter within the distal amino-terminal tail of the receptor. These data are consistent with affinity labeling of other members of the class B G protein-coupled receptors using analogous probes and may suggest a common ligand binding mechanism for this family.

Editorial

The papers in this issue of Peptide Science reflect the scientific identity of the journal, as well as the truly international character of the field of peptide chemistry and biology. We are very pleased to present a review solicited from one of the recipients of the 2004 Vincent du Vigneaud Awards from the American Peptide Society. Dieter Seebach of the ETH, Zurich, was honored for “the discovery of peptides consisting of homologated proteinogenic amino acids and of their unexpected chemical, structural, and biological properties.” His review in this issue provides an extensive discussion of β-amino acids, specifically those with side chains in the carbonyl position, including their occurrence in nature, their synthesis, and their uses in design of novel peptide properties. We congratulate Dieter for this richly deserved recognition, and we thank him for providing an exciting review to Peptide Science. The original papers appearing in this issue epitomize the field of peptide science and illustrate the power of peptide synthesis and conformational study: Chakrabarty and coworkers present results of peptide design aimed at deducing the principles for helical bundle formation. Their work explores factors important in packing of α-helices and shows how peptide studies can shed light on fundamental ‘rules’ for the formation of protein architectures. The use of synthetic peptides to elucidate the origins of biological activity is the theme of the paper contributed by Epand and coworkers, who are exploring how the biological activity of calcitonin analogues correlates with their biophysical properties. Lastly, Alix and coworkers present synergistic experimental and computational studies of the conformational preferences of short peptides responsible for the elasticity of elastin, a major component of the extracellular matrix.

Preface

This study evaluates the biological effects caused in healthy males by administration by the endonasal route of 50 IU and 100 IU of salmon calcitonin and 40 IU of carbocalcitonin or (Asu 1.7 eCT), an aminosuberic analogue of eel calcitonin. The comparison among calcitonins administred shows an absorption of carbocalcitonin greater than 50%, still measurable at 240th minute, while the absorptions of salmon calcitonin are shorter. The efficacy of absorption of carbocalcitonin is demonstrated by the magnitude of the biological effects such as decrease of total serum calcium and increase of cAMP.