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Abstract
Bioassay procedures have been the prerequisite for detection, purification, elucidation of the structure and the synthesis of neurohypophysial hormones. After a review of the history of these bioassays and of the standard preparations including international standards, the current international standards and the bioassay methods prescribed by the pharmacopoeias are described. Some important methodological details are also mentioned.
... The use of peptides for human therapeutic began with peptides such as insulin and adrenocorticotrophic hormone (ACTH) isolated from natural sources in the first half of the 20th century (Banting et al., 1922). Further, with sequence elucidation and chemical synthesis of peptides in the 1950s, synthetic oxytocin and vasopressin entered to clinical use (Stürmer, 1989). ...
DEVELOPING BIOACTIVE MATERIALS FOR DENTAL APPLICATIONS
... The use of peptides for human therapeutic began with peptides such as insulin and adrenocorticotrophic hormone (ACTH) isolated from natural sources in the first half of the 20th century (Banting et al., 1922). Further, with sequence elucidation and chemical synthesis of peptides in the 1950s, synthetic oxytocin and vasopressin entered to clinical use (Stürmer, 1989). ...
Regenerative therapy in oral tissues has gained relevance since tissue loss due to congenital or acquired diseases as well as trauma is a major health problem worldwide. Regeneration depends on the natural capacity of the body and the use of biomaterials and bioactive molecules that can module the processes to replace lost or damaged tissues and restore function. The combined use of scaffolds, cells, and bioactive molecules such as peptides is considered the best approach to achieve tissue regeneration. These peptides can induce diverse cellular processes as they can influence cell behavior and also can modify scaffold properties, giving as a result the enhancement of cell adhesion, proliferation, migration, differentiation, and biomineralization that are required given the complex nature of oral tissues. Specifically, synthetic peptides (SP) have a positive influence on scaffold biocompatibility since in many cases they can mimic the function of a natural peptide or a full-length protein. Besides, they are bioactive molecules easy to produce, process, and modify, and they can be prepared under well-defined and controlled conditions. This review aims to compile the most relevant information regarding advances in SP for dental and periodontal tissue regeneration, their biological effects, and their clinical implications. Even though most of the SP are still under investigation, some of them have been studied in vitro and in vivo with promising results that may lead to preclinical studies. Besides there are SP that have shown their efficacy in clinical trials such as P11-4 for enamel regeneration or caries prevention and ABM/P-15 for cementum, periodontal ligament (PDL), and alveolar bone on a previously calculus- and biofilm-contaminated zone. Also, some SP are commercially available such as PTH1-34 and PepGen P-15 which are used for bone defects treatment.
Currently, it remains unclear which specific peptides could be appropriate for applications in different fields of dentistry. The aim of this scoping review was to scan the contemporary scientific papers related to the types, uses and applications of peptides in dentistry at the moment. Literature database searches were performed in the following databases: PubMed/MEDLINE, Scopus, Web of Science, Embase, and Scielo. A total of 133 articles involving the use of peptides in dentistry-related applications were included. The studies involved experimental designs in animals, microorganisms, or cells; clinical trials were also identified within this review. Most of the applications of peptides included caries management, implant osseointegration, guided tissue regeneration, vital pulp therapy, antimicrobial activity, enamel remineralization, periodontal therapy, the surface modification of tooth implants, and the modification of other restorative materials such as dental adhesives and denture base resins. The in vitro and in vivo studies included in this review suggested that peptides may have beneficial effects for treating early carious lesions, promoting cell adhesion, enhancing the adhesion strength of dental implants, and in tissue engineering as healthy promotors of the periodontium and antimicrobial agents. The lack of clinical trials should be highlighted, leaving a wide space available for the investigation of peptides in dentistry.
Anti-diuretic peptides are widely used for the control of body water balance. With the growing concerns on their pharmacological characteristics and clinical safety, there is an increasing request of sensitive, selective and robust analytical assays for the determination of anti-diuretics in biological samples. This article provides a perspective review of various methodologies developed and validated in the past, including immunoassay (IA), high performance liquid chromatography (HPLC) and capillary electrophoresis (CE), with detections of radio, UV, fluorescence and mass spectrometry. Systematic description of each technique was given and emphasis was laid on the problems encountered with each assay. Despite the infrequent application of mass spectrometry in anti-diuretics quantitative analysis, it was highlighted here for its remarkable sensitivity and selectivity. The ultimate aim of this review is to demonstrate the analytical options of peptide determination and promote the quantification of peptide-like drugs and biomarkers in respect to fast-expanding peptide market and therapeutics.
The glutamine(4) residue in [deamino-Cys(1)]arginine vasopressin (dAVP) was replaced by a broad series of aliphatic, aromatic, polar, and charged amino acids to give the following peptides: d[Gly(4)]AVP (1), d[Ala(4)]AVP (2), d[Abu(4)]AVP (3), d[Nva(4)]AVP (4), d[Nle(4)]AVP (5), d[Leu(4)]AVP (6), d[Ile(4)]AVP (7), d[Thi(4)]AVP (8), d[Phe(4)]AVP (9), d[Tyr(4)]AVP (10), d[Trp(4)]AVP (11), d[Asn(4)]AVP (12), d[Ser(4)]AVP (13), d[Thr(4)]AVP (14), d[Dap(4)]AVP (15), d[Dab(4)]AVP (16), d[Orn(4)]AVP (17), d[Lys(4)]AVP (18), d[Arg(4)]AVP (19), d[Har(4)]AVP (20), and d[Glu(4)]AVP (21). All peptides were synthesized by solid-phase methods using BOC chemistry for all but one peptide (8), which required the use of Fmoc chemistry. The binding and functional properties of these position 4 substituted analogues of dAVP (d[X(4)]AVP) and the previously reported d[Cha(4)]AVP (Derick et al. Endocrinology 2002, 143, 4655-4664) were evaluated on human arginine vasopressin (AVP) V(1a), V(1b), and V(2) receptors and on the human oxytocin (OT) receptor expressed in living Chinese hamster ovary (CHO) cells. Binding studies revealed that broad modifications of the fourth residue of dAVP do not significantly alter affinity for the human V(1b) receptor. Only aromatic (Phe, Tyr, Trp) or negatively charged (Glu) residues reduce V(1b) affinity. By contrast, the human V(1a) and more particularly the human V(2) and the OT receptors are more sensitive to many of these modifications. Thus, the replacement of the Gln(4) residue of dAVP by aliphatic (Leu, Cha) or positively charged (Orn, Lys, Arg, Har) amino acids led to analogues exhibiting drastic reductions of their affinity for the human V(1a), V(2), and OT receptors. Consequently, in addition to the previously reported d[Cha(4)]AVP, peptides 6 and 17-20 display excellent selectivities for the human V(1b) receptor. The key structural requirement responsible for optimal V(1b) selectivity appears to be the length and branching of the aliphatic side chain of the fourth residue of dAVP. Functional studies performed on CHO cells expressing the different human AVP/OT receptors confirm the V(1b) selectivity of peptides 6, 17, 18, 20, and d[Cha(4)]AVP. However, d[Arg(4)]AVP (19), which triggers an excellent coupling between the human V(2) receptor and adenylyl cyclase, was found to exhibit both V(1b) and V(2) agonism in functional tests. More interestingly, these functional experiments revealed that, depending on the AVP/OT receptor, a given d[X(4)]AVP analogue may behave as a full agonist or as a partial agonist. This strongly suggests that the fourth residue of dAVP plays an important role in the coupling between the hormone-receptor complex, the heterotrimeric G protein, and the effectors. In conclusion, the synthesis of these d[X(4)]AVP analogues led to the discovery of new V(1b) agonists with high affinity and greatly enhanced selectivities. Thus, in addition to d[Cha(4)]AVP, d[Leu(4)]AVP (6), d[Orn(4)]AVP (17), d[Lys(4)]AVP (18), and d[Har(4)]AVP (20) are useful new tools for studying the structure and the function of the human V(1b) receptor.
Single rats rendered diuretic by water, and alcohol in sedative dosage, constitute a satisfactory biologic test for the antidiuretic action of pitressin. It is 10 times more sensitive than Walker's3 test, in which he used the diuretic rabbit; however, the required dose of pitressin per kilogram of animal is essentially the same. As an assay technic, using the same number of injections, ours is at least as reliable as the multiple rat test of Burn, 1 and as other tests available for antidiuretic substances.
The bioassay of active substances from the posterior pituitary is just as necessary today as it was 55 years ago when Dale and Laidlaw introduced the guinea-pig uterus method. Unfortunately, what Dale and Laidlaw regretfully admitted in 1912 is also valid: “There seems no prospect at present of the control of its (the posthypophysial extract’s) efficiency by chemical methods”, even though the complex octapeptide structure of the posthypophysial hormones has since been elucidated and confirmed by synthesis.
The following analogues of oxytocin and lysine-vasopressin have been synthesized: Tyr3-oxytocin, Phe2-Phe3-oxytocin, Phe2-Tyr3-oxytocin, Phe2-Lys8-vasopressin, Tyr3-Lys8-vasopressin, Phe2-Tyr3-Lys8-vasopressin.
IN 1910, Ott and Scott (1,2) discovered that the injection of an extract of the posterior lobe of the pituitary into a lactating goat caused the contraction of theglands and the discharge of milk. These results were quickly confirmed with lactating cats and dogs (3), with dairy cattle (4) and with women (5). As is the case of other effects of the posterior pituitary extracts, there has long been a question whether the factors involved were true hormones and played a normal role in the removal of milk at nursing or milking time or whether pituitrin had only a pharmacological action on certain types of smooth muscle including those present in the mammary gland.
It has been known for many years that the injection of pituitrin causes the contraction of the mammary gland and permits the removal of milk which is otherwise unavailable (6).
Zusammenfassung Die Synthese und die pharmakologischen Haupteigenschaften von Orn8-Vasopressin, Phe2-Orn8-Vasopressin, Orn8-Oxytocin und Phe2-Orn8-Oxytocin werden beschrieben. Die pressorische Aktivität dieser Peptide zeigt eine in der Reihenfolge zunehmende Selektivität.
In October 1955, stocks of the Second International Standard for Posterior Pituitary were running low and the Department of Biological Standards of the National Institute for Medical Research, London, was asked to proceed with the arrangements for an international collaborative assay of material for the Third Standard. A single 142-g batch of posterior-pituitary-lobe powder was obtained and distributed in ampoules, in approximately 30-mg quantities. Samples were sent to 19 laboratories in 10 countries. In all, 185 assays were carried out, 122 for oxytocic activity, 53 for vasopressor activity and 10 for antidiuretic activity.On the basis of the results, which were analysed statistically at the National Institute for Medical Research, it was agreed that the potency of the Third Standard (re-named International Standard for Oxytocic, Vasopressor and Antidiuretic Substances in 1956, in view of the recent synthesis of oxytocin and vasopressin) should be expressed as 2.0 International Units per milligram. The International Unit therefore remains unchanged as 0.5 mg of the dry powder.
The biological activity of synthetic polypeptides containing the amino acids of natural pure trypsin-bradykinin and snake-venom-bradykinin has been investigated. A series of tests for bradykinin-like activity in stimulating plain muscle, depressing the blood pressure and increasing capillary permeability was used on various species. A nonapeptide with the following structure: H-L-Arg-L-Pro-L-Pro-Gly-L-Phe-L-Ser-L-Pro-L-Phe-L-Arg-OH elicited qualitatively and quantitatively the effects of the pure natural bradykinins. An octapeptide with the following structure: H-L-Arg-L-Pro-Gly-L-Phe-L-Ser-L-Pro-L-Phe-L-Arg-OH also exerted bradykinin-like effects but was 50 to 100 times less active than the nonapeptide. Three other octapeptides and a heptapeptide were without any significant effect. Further work will demonstrate if the nonapeptide A is synthetic bradykinin or a peptide with bradykinin-like activity.
Note added since submission of this paper: The data from this investigation were personally precommunicated to Elliott, Lewis, and Horton, who have since found that the structure of pure trypsin-bradykinin is identical with the structure of the nonapeptide A. Therefore, this synthetic nonapeptide is in fact synthetic bradykinin.
Handbook of Experimental Pharmacology
- Stürmer