The Long Way of Oxytocin from the Uterus to the Heart in 70 Years from Its Discovery.

The research program on oxytocin started in 1895, when Oliver and Schafer reported that a substance extracted from the pituitary gland elevates blood pressure when injected intravenously into dogs. Dale later reported that a neurohypophysial substance triggers uterine contraction, lactation, and antidiuresis. Purification of this pituitary gland extracts revealed that the vasopressor and antidiuretic activity could be attributed to vasopressin, while uterotonic and lactation activity could be attributed to oxytocin. In 1950, the amino-acid sequences of vasopressin and oxytocin were determined and chemically synthesized. Vasopressin (CYFQNCPRG-NH2) and oxytocin (CYIQNCPLG-NH2) differ by two amino acids and have a disulfide bridge between the cysteine residues at position one and six conserved in all vasopressin/oxytocin-type peptides. This characterization of oxytocin led to the Nobel Prize awarded in 1955 to Vincent du Vigneaud. Nevertheless, it was only 50 years later when the evidence that mice depleted of oxytocin or its receptor develop late-onset obesity and metabolic syndrome established that oxytocin regulates energy and metabolism. Oxytocin is anorexigenic and regulates the lean/fat mass composition in skeletal muscle. Oxytocin's effect on muscle is mediated by thermogenesis via a pathway initiated in the myocardium. Oxytocin involvement in thermogenesis and muscle contraction is linked to Prader-Willi syndrome in humans, opening exciting therapeutic avenues.

Vasopressin and Its Analogues: From Natural Hormones to Multitasking Peptides.

Human neurohormone vasopressin (AVP) is synthesized in overlapping regions in the hypothalamus. It is mainly known for its vasoconstricting abilities, and it is responsible for the regulation of plasma osmolality by maintaining fluid homeostasis. Over years, many attempts have been made to modify this hormone and find AVP analogues with different pharmacological profiles that could overcome its limitations. Non-peptide AVP analogues with low molecular weight presented good affinity to AVP receptors. Natural peptide counterparts, found in animals, are successfully applied as therapeutics; for instance, lypressin used in treatment of diabetes insipidus. Synthetic peptide analogues compensate for the shortcomings of AVP. Desmopressin is more resistant to proteolysis and presents mainly antidiuretic effects, while terlipressin is a long-acting AVP analogue and a drug recommended in the treatment of varicose bleeding in patients with liver cirrhosis. Recently published results on diverse applications of AVP analogues in medicinal practice, including potential lypressin, terlipressin and ornipressin in the treatment of SARS-CoV-2, are discussed.

An oxytocin/vasopressin-related neuropeptide modulates social foraging behavior in the clonal raider ant.

Oxytocin/vasopressin-related neuropeptides are highly conserved and play major roles in regulating social behavior across vertebrates. However, whether their insect orthologue, inotocin, regulates the behavior of social groups remains unknown. Here, we show that in the clonal raider ant Ooceraea biroi, individuals that perform tasks outside the nest have higher levels of inotocin in their brains than individuals of the same age that remain inside the nest. We also show that older ants, which spend more time outside the nest, have higher inotocin levels than younger ants. Inotocin thus correlates with the propensity to perform tasks outside the nest. Additionally, increasing inotocin pharmacologically increases the tendency of ants to leave the nest. However, this effect is contingent on age and social context. Pharmacologically treated older ants have a higher propensity to leave the nest only in the presence of larvae, whereas younger ants seem to do so only in the presence of pupae. Our results suggest that inotocin signaling plays an important role in modulating behaviors that correlate with age, such as social foraging, possibly by modulating behavioral response thresholds to specific social cues. Inotocin signaling thereby likely contributes to behavioral individuality and division of labor in ant societies.

Dynamics and structural communication in the ternary complex of fully phosphorylated V2 vasopressin receptor, vasopressin, and ß-arrestin 1.

G protein-coupled receptors (GPCRs) are critically regulated by arrestins, which not only desensitize G-protein signaling but also initiate a G protein-independent wave of signaling. The information from structure determination was herein exploited to build a structural model of the ternary complex, comprising fully phosphorylated V2 vasopressin receptor (V2R), the agonist arginine vasopressin (AVP), and ß-arrestin 1 (ß-arr1). Molecular simulations served to explore dynamics and structural communication in the ternary complex. Flexibility and mechanical profiles reflect fold of V2R and ß-arr1. Highly conserved amino acids tend to behave as hubs in the structure network and contribute the most to the mechanical rigidity of V2R seven-helix bundle and of ß-arr1. Two structurally and dynamically distinct receptor-arrestin interfaces assist the twist of the N- and C-terminal domains (ND and CD, respectively) of ß-arr1 with respect to each other, which is linked to arrestin activation. While motion of the ND is essentially assisted by the fully phosphorylated C-tail of V2R (V2RCt), that of CD is assisted by the second and third intracellular loops and the cytosolic extensions of helices 5 and 6. In the presence of the receptor, the ß-arr1 inter-domain twist angle correlates with the modes describing the essential subspace of the ternary complex. ß-arr1 motions are also influenced by the anchoring to the membrane of the C-edge-loops in the ß-arr1-CD. Overall fluctuations reveal a coupling between motions of the agonist binding site and of ß-arr1-ND, which are in allosteric communication between each other. Mechanical rigidity points, often acting as hubs in the structure network and distributed along the main axis of the receptor helix bundle, contribute to establish a preferential communication pathway between agonist ligand and the ND of arrestin. Such communication, mediated by highly conserved amino acids, involves also the first amino acid in the arrestin C-tail, which is highly dynamic and is involved in clathrin-mediated GPCR internalization.

Cone snail analogs of the pituitary hormones oxytocin/vasopressin and their carrier protein neurophysin. Proteomic and transcriptomic identification of conopressins and conophysins.

Transcriptomic analysis of cone snail venom duct tissue has permitted the identification of diverse conopressin/conophysin precursor sequences from seven distinct Conus species. Multiple precursor isoforms are present in C.monile, C.lividus and C.loroisii. Aqueous extracts of the venom duct tissue from C.monile yield a band, at ~ 15-20 kDa on SDS-PAGE. In-gel trypsin digestion, followed by mass spectrometry establishes the presence of two distinct conopressin/conophysin isoforms that differ at position 8 in the predicted conopressin nonapeptide sequence. Mass spectrometric analysis of aqueous extracts revealed the presence of four conopressin related peptides, whose sequences could be deduced from MS/MS fragmentation patterns. The four sequences determined in this study are CFIRNCPKG*, CFIRNCPEG*, CFIRNCPK* and CFIRNCPE* (∗ indicates amide), which were further confirmed by comparison with chemically synthesized peptides. A conophysin with a mass of 9419.7 Da was also detected, corresponding to one of the isoforms revealed by the transcriptome data. Complete conservation of fourteen Cys residues and the key residues involved in peptide hormone binding is established by comparison of conophysin sequences, with the crystallographically characterized sequence of bovine neurophysin, in complex with vasopressin. A survey of available sequences for oxytocin/vasopressin peptides in both vertebrates and invertebrates establishes the conopressins as a distinct group in this family. C-terminal amidated, truncated conopressin analogs may arise by alternate post-translational processing.

In Silico Studies on Anti-Stress Compounds of Ethanolic Root Extract of Hemidesmus indicus L.

BACKGROUND: Alternative medicine is available for those diseases which cannot be treated by conventional medicine. Ayurveda and herbal medicines are important alternative methods in which the treatment is done with extracts of different medicinal plants. This work is concerned with the evaluation of anti-stress bioactive compounds from the ethanolic root extract of Hemidesmus indicus. METHODS: Gas chromatography and Mass Spectrum studies are used to identify the compounds present in the ethanolic extract based on the retention time, area. In order to perform docking studies, Vasopressin model is generated using modeling by Modeller 9v7. Vasopressin structure is developed based on the crystal structure of neurophysin-oxytocin from Bos taurus (PDB ID: 1NPO_A) collected from the PDB data bank. Using molecular dynamics simulation methods, the final predicted structure is obtained and further analyzed by verifying 3D and PROCHECK programs, confirmed that the final model is reliable. The identified compounds are docked to vasopressin for the prediction of anti-stress activity using GOLD 3.0.1 software. RESULTS: The predicted model of Vasopressin structure is stabilized and confirmed that it is a reliable structure for docking studies. The results indicated ARG4, THR7, ASP9, ASP26, ALA32, ALA 80 in Vasopressin are important determinant residues in binding as they have strong hydrogen bonding with phytocompounds. Among the 21 phytocompounds identified and docked, molecule Deoxiinositol, pentakis- O-(trimethylsilyl) showed the best docking results with Vasopressin. CONCLUSION: The identified compounds were used for anti-stress activity by insilico method with Vasopressin which plays an important role in causing stress and hence selected for inhibitory studies with phytocompounds. The phytocompounds are inhibiting vasopressin through hydrogen bodings and are important in protein-ligand interactions. Docking results showed that out of twenty-one compounds, Deoxiinositol, pentakis-O-(trimethylsilyl) showed best docking energy to the Vasopressin.

I8-arachnotocin-an arthropod-derived G protein-biased ligand of the human vasopressin V2 receptor.

The neuropeptides oxytocin (OT) and vasopressin (VP) and their G protein-coupled receptors OTR, V1aR, V1bR, and V2R form an important and widely-distributed neuroendocrine signaling system. In mammals, this signaling system regulates water homeostasis, blood pressure, reproduction, as well as social behaviors such as pair bonding, trust and aggression. There exists high demand for ligands with differing pharmacological profiles to study the physiological and pathological functions of the individual receptor subtypes. Here, we present the pharmacological characterization of an arthropod (Metaseiulus occidentalis) OT/VP-like nonapeptide across the human OT/VP receptors. I8-arachnotocin is a full agonist with respect to second messenger signaling at human V2R (EC50 34 nM) and V1bR (EC50 1.2 µM), a partial agonist at OTR (EC50 790 nM), and a competitive antagonist at V1aR [pA2 6.25 (558 nM)]. Intriguingly, I8-arachnotocin activated the Gαs pathway of V2R without recruiting either ß-arrestin-1 or ß-arrestin-2. I8-arachnotocin might thus be a novel pharmacological tool to study the (patho)physiological relevance of ß-arrestin-1 or -2 recruitment to the V2R. These findings furthermore highlight arthropods as a novel, vast and untapped source for the discovery of novel pharmacological probes and potential drug leads targeting neurohormone receptors.

Mutational Basin-Hopping: Combined Structure and Sequence Optimization for Biomolecules.

The study of energy landscapes has led to a good understanding of how and why proteins and nucleic acids adopt their native structure. Through evolution, sequences have adapted until they exhibit a strongly funneled energy landscape, stabilizing the native fold. Design of artificial biomolecules faces the challenge of creating similar stable, minimally frustrated, and functional sequences. Here we present a biminimization approach, mutational basin-hopping, in which we simultaneously use global optimization to optimize the energy and a target function describing a desired property of the system. This optimization of structure and sequence is a generalized basin-hopping method and produces an efficient design process, which can target properties such as binding affinity or solubility.

Impact of estrogen and photoperiod on arginine vasotocin and VT3 receptor expression in the shell gland of quail.

Role of estrogen and photoperiod is well-established in avian reproduction. In addition, the distribution and the expression of arginine vasotocin (AVT) and its receptor VT3 to ensure reproductive/breeding conditions in Japanese quail influenced by them has been the main focus of this review. To consider this aspect the mRNA expression of VT3 receptor and its ligand AVT in the shell gland has been emphasized. In birds, AVT performs a dual role as an anti-diuretic hormone and the functions accomplished by oxytocin in mammals. The physiological actions of AVT in birds are mediated through its diverse receptor subtypes VT1, VT2, VT3 and VT4.  Dynamic alteration of VT3 expression during different reproductive and photo-sexual conditions of quail can be modulated by estrogen. In addition to the endocrine effect of AVT, the shell gland is complemented by its paracrine action via its receptors. Evidences indicate that the expression of shell gland AVT modulated by estrogen appears to play a priming role by modulating the availability of VT3 receptor for the required action of neurohypophysial AVT during oviposition.

Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs.

Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.

Search of vasopressin analogs with antiproliferative activity on small-cell lung cancer: drug design based on two different approaches.

AIM: Development of compounds with therapeutic application requires the interaction of different disciplines. Several tumors express vasopressin (AVP; arginine vasopressin) receptors with contrasting effects depending on receptor subtype. Desmopressin (dDAVP) is an AVP-selective analog with antiproliferative properties. In this work, an evolutionary approach and a rational strategy were applied in order to design novel AVP analogs. RESULTS: We designed two novel analogs; dDInotocin (dDINT, insect analog), and [V4Q5]dDAVP, and demonstrated the importance of the dDAVP conformational loop for its antiproliferative activity. [V4Q5] dDAVP showed major cytostatic effect on lung cancer cells than dDAVP and its cytostatic effect was abolished by V2R blockade. CONCLUSION: Combination of these strategies could provide the basis for future studies for the development of improved compounds with potential therapeutic applications.

Dystrophin 71 and α1syntrophin in morpho-functional plasticity of rat supraoptic nuclei: Effect of saline surcharge and reversibly normal hydration.

Dystrophin (Dp) is a multidomain protein that links the actin cytoskeleton to the extracellular matrix through the dystrophin associated proteins complex (DAPC). Dp of 71 kDa (Dp71), corresponding to the COOH-terminal domain of dystrophin, and α1-syntrophin (α1Syn) as the principal component of the DAPC, are strongly expressed in the brain. To clarify their involvement in the central control of osmotic homeostasis, we investigated the effect of 14 days of salt loading (with drinking water containing 2% NaCl) and then reversibly to 30 days of normal hydration (with drinking water without salt), first on the expression by western-blotting and the distribution by immunochemistry of Dp71 and α1Syn in the SON of the rat and, second, on the level of some physiological parameters, as the plasma osmolality, natremia and hematocrit. Dp71 is the most abundant form of dystrophin revealed in the supraoptic nucleu (SON) of control rat. Dp71 was localized in magnocellular neurons (MCNs) and astrocytes, when α1Syn was observed essentially in astrocytes end feet. After 14 days of salt-loading, Dp71 and α1Syn signals decreased and a dual signal for these two proteins was revealed in the astrocytes processes SON surrounding blood capillaries. In addition, salt loading leads to an increase in plasma osmolality, natremia and hematocrit. Reversibly, after 30 days of normal hydration, the intensity of the signal for the two proteins, Dp71 and α1Syn, increased and approached that of control. Furtheremore, the levels of the physiological parameters decreased and approximated those of control. This suggests that Dp71 and α1Syn may be involved in the functional activity of the SON. Their localization in astrocyte end feet emphasizes their importance in neuronal-vascular-astrocyte interactions for the central detection of osmolality. In the SON, Dp71 and α1Syn may be involved in osmosensitivity.

[Small cell lung cancer associated with multiple paraneoplastic syndromes].

We report the case of a patient presenting with multiple severe electrolyte disturbances who was subsequently found to have small cell lung cancer. Upon further evaluation, she demonstrated three distinct paraneoplastic processes, including the syndrome of inappropriate antidiuretic hormone, Fanconi syndrome, and an inappropriate elevation in fibroblast growth factor-23 (FGF23). The patient underwent one round of chemotherapy, but she was found to have progressive disease. After 36 days of hospitalization, the patient made the decision to enter hospice care and later she expired.

Vasopressin-induced serine 269 phosphorylation reduces Sipa1l1 (signal-induced proliferation-associated 1 like 1)-mediated aquaporin-2 endocytosis.

The abundance of integral membrane proteins in the plasma membrane is determined by a dynamic balance between exocytosis and endocytosis, which can often be regulated by physiological stimuli. Here, we describe a mechanism that accounts for the ability of the peptide hormone vasopressin to regulate water excretion via a phosphorylation-dependent modulation of the PDZ domain-ligand interaction involving the water channel protein aquaporin-2. We discovered that the PDZ domain-containing protein Sipa1l1 (signal-induced proliferation-associated 1 like 1) binds to the cytoplasmic PDZ-ligand motif of aquaporin-2 and accelerates its endocytosis in the absence of vasopressin. Vasopressin-induced aquaporin-2 phosphorylation within the type I PDZ-ligand motif disrupted the interaction, in association with reduced aquaporin-2 endocytosis and prolonged plasma membrane aquaporin-2 retention. This phosphorylation-dependent alteration in the PDZ domain-ligand interaction was explained by 3D structural models, which showed a hormone-regulated mechanism that controls osmotic water transport and systemic water balance in mammals.

Direct MALDI-MS analysis of the disulfide bonds in peptide using thiosalicylic acid as a reactive matrix.

The ability of a thiol-containing molecule, thiosalicylic acid (TSA), to function as a reactive matrix for matrix-assisted laser desorption/ionization (MALDI) mass spectrometry analysis of peptides has been investigated. Although TSA has reducing characteristics, the use of TSA did not cause a reduction-induced MALDI in-source decay, probably because of the weak interactions between the thiol group in TSA and the carboxyl oxygen in the peptide. In contrast, when peptides containing disulfide bonds were analyzed by MALDI with TSA as the matrix, the disulfide bond was partially cleaved owing to the reaction with TSA, producing TSA-adducted peptides. The reaction between the disulfide bond and TSA was suggested to be occurred in solution. The comparison of the MALDI mass spectra obtained using conventional matrix and TSA allows us to count the number of disulfide bonds in the peptides. Copyright © 2017 John Wiley & Sons, Ltd.

Small cell lung cancer associated with multiple paraneoplastic syndromes / Cáncer de pulmón de células pequeñas asociado a múltiples síndromes paraneoplásicos

Abstracts We report the case of a patient presenting with multiple severe electrolyte disturbances who was subsequently found to have small cell lung cancer. Upon further evaluation, she demonstrated three distinct paraneoplastic processes, including the syndrome of inappropriate antidiuretic hormone, Fanconi syndrome, and an inappropriate elevation in fibroblast growth factor-23 (FGF23). The patient underwent one round of chemotherapy, but she was found to have progressive disease. After 36 days of hospitalization, the patient made the decision to enter hospice care and later she expired.

Resumen Se reporta el caso de una paciente que ingresó al hospital para evaluación de múltiples trastornos electrolíticos y, posteriormente, se le hizo el diagnóstico de cáncer de pulmón de células pequeñas. Tras la evaluación médica, se detectaron tres síndromes paraneoplásicos: síndrome de secreción inadecuada de hormona antidiurética, síndrome de Fanconi y elevación inapropiada del factor 23 de crecimiento de fibroblastos. Se le administró quimioterapia sin éxito, por lo cual se decidió darle tratamiento paliativo y, un tiempo después, falleció.

Dilute versus concentrated vasopressin administration during laparoscopic myomectomy: a randomised controlled trial.

OBJECTIVE: To determine if higher-volume, fixed-dose administration of vasopressin further reduces blood loss at the time of minimally invasive myomectomy. DESIGN: Randomised multicentre clinical trial. SETTING: Tertiary-care academic centres in the USA. POPULATION: Women undergoing conventional laparoscopic or robot-assisted laparoscopic myomectomy. METHODS: All participants received the same 10-unit (U) dose of vasopressin, but were randomly assigned to one of two groups: (i) received 200 ml of diluted vasopressin solution (20 U in 400 ml normal saline), and (ii) received 30 ml of concentrated vasopressin solution (20 U in 60 ml normal saline). MAIN OUTCOME MEASURES: The primary study outcome was estimated blood loss; the study was powered to detect a 100-ml difference. RESULTS: A total of 152 women were randomised; 76 patients in each group. Baseline demographics were similar between groups. The primary outcome of intraoperative blood loss was not significantly different, as measured by three parameters: surgeon estimate (mean estimated blood loss 178 ± 265 ml and 198 ± 232 ml, dilute and concentrated groups respectively, P = 0.65), suction canister-calculated blood loss, or change in haematocrit levels. There were no vasopressin-related adverse events. CONCLUSION: Both dilute and concentrated vasopressin solutions that use the same drug dosing demonstrate comparable safety and tolerability when administered for minimally invasive myomectomy; however, higher volume administration of vasopressin does not reduce blood loss. TWEETABLE ABSTRACT: This randomised trial failed to show benefit of high-volume dilute vasopression.

Continuous and selective measurement of oxytocin and vasopressin using boron-doped diamond electrodes.

The electrochemical detection of oxytocin using boron-doped diamond (BDD) electrodes was studied. Cyclic voltammetry of oxytocin in a phosphate buffer solution exhibits an oxidation peak at +0.7 V (vs. Ag/AgCl), which is attributable to oxidation of the phenolic group in the tyrosyl moiety. Furthermore, the linearity of the current peaks obtained in flow injection analysis (FIA) using BDD microelectrodes over the oxytocin concentration range from 0.1 to 10.0 µM with a detection limit of 50 nM (S/N = 3) was high (R(2) = 0.995). Although the voltammograms of oxytocin and vasopressin observed with an as-deposited BDD electrode, as well as with a cathodically-reduced BDD electrode, were similar, a clear distinction was observed with anodically-oxidized BDD electrodes due to the attractive interaction between vasopressin and the oxidized BDD surface. By means of this distinction, selective measurements using chronoamperometry combined with flow injection analysis at an optimized potential were demonstrated, indicating the possibility of making selective in situ or in vivo measurements of oxytocin.

Investigation of Elemental Mass Spectrometry in Pharmacology for Peptide Quantitation at Femtomolar Levels.

In the search of new robust and environmental-friendly analytical methods able to answer quantitative issues in pharmacology, we explore liquid chromatography (LC) associated with elemental mass spectrometry (ICP-MS) to monitor peptides in such complex biological matrices. The novelty is to use mass spectrometry to replace radiolabelling and radioactivity measurements, which represent up-to now the gold standard to measure organic compound concentrations in life science. As a proof of concept, we choose the vasopressin (AVP)/V1A receptor system for model pharmacological assays. The capacity of ICP-MS to provide highly sensitive quantitation of metallic and hetero elements, whatever the sample medium, prompted us to investigate this technique in combination with appropriate labelling of the peptide of interest. Selenium, that is scarcely present in biological media, was selected as a good compromise between ICP-MS response, covalent tagging ability using conventional sulfur chemistry and peptide detection specificity. Applying selenium monitoring by elemental mass spectrometry in pharmacology is challenging due to the very high salt content and organic material complexity of the samples that produces polyatomic aggregates and thus potentially mass interferences with selenium detection. Hyphenation with a chromatographic separation was found compulsory. Noteworthy, we aimed to develop a straightforward quantitative protocol that can be performed in any laboratory equipped with a standard macrobore LC-ICP-MS system, in order to avoid time-consuming sample treatment or special implementation of instrumental set-up, while allowing efficient suppression of all mass interferences to reach the targeted sensitivity. Significantly, a quantification limit of 57 ng Se L-1 (72 femtomoles of injected Se) was achieved, the samples issued from the pharmacological assays being directly introduced into the LC-ICP-MS system. The established method was successfully validated and applied to the measurement of the vasopressin ligand affinity for its V1A receptor through the determination of the dissociation constant (Kd) which was compared to the one recorded with conventional radioactivity assays.

Analysis of argentinated peptide complexes using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry: Peptide = oxytocin, arg(8) -vasopressin, bradykinin, bombesin, somatostatin, neurotensin.

RATIONALE: The increased use of silver nanoparticles (AgNPs) for various biological applications, and over-expression of various peptide receptors in different tumors/cancer cells, necessitate the need for dedicated investigations on the intrinsic binding ability of Ag with various biologically important peptides for better understanding of AgNPs-peptide interactions and for the future development of contrasting agents as well as drugs for imaging/biomedical applications. METHODS: The [M+(Ag)n ](+) complexes are prepared and characterized using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). RESULTS: Silver complexes of the peptides [M+(Ag)n ](+) , where M = oxytocin, arg(8) -vasopressin, bradykinin, bombesin, somatostatin, and neurotensin, have been investigated for their intrinsic Ag(+) -binding ability. Unusual binding of up to seven Ag(+) with these small peptides is observed. The mass spectra show n = 1-5 for bombesin and somatostatin, n = 1-6 for bradykinin and arg(8) -vasopressin, and n = 1-7 for oxytocin and neurotensin. In addition, oxytocin and arg(8) -vasopressin show the formation of dimers and their complexes [M2 +(Ag)n ](+) with n = 1-8 and n = 1-5, respectively. The possible amino acid residues responsible for Ag(+) binding in each peptide have been identified on the basis of density functional theory (DFT)-calculated binding energy values of Ag(+) towards individual amino acids. CONCLUSIONS: Mass spectrometric evidence indicates that the peptides, viz., oxytocin, arg(8) -vasopressin, bradykinin, bombesin, somatostatin, and neurotensin, show greater affinity for Ag(+) . Hence, they may be used as carriers for AgNPs in targeted drug delivery as well as an alternative for iodinated contrasting agents in dual energy X-ray imaging techniques. Radio-labeled Ag with these peptides can also be used in radio-pharmaceuticals for diagnostic and therapeutic applications. Copyright © 2016 John Wiley & Sons, Ltd.