Directional thyroid hormone distribution via the blood stream to target sites

Publication date: Available online 28 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Susanne T. Janssen, Onno E. Janssen
Thyroid hormones are bound to three major serum transport proteins, thyroxin-binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). TBG has the strongest affinity for thyroid hormones, TTR is also found in the cerebrospinal fluid and HSA is the most abundant protein in plasma. Combination defects of either a high affinity TTR or HSA variant do not compensate TBG deficiency, underscoring the dominant role of TBG among the thyroid hormone transport proteins. On the other hand, coexistence of raised affinity TTR and HSA variants causes an augmented hyperthyroxinemia. Variations in thyroid hormone transport proteins may alter thyroid function tests to mimic hypo- or hyperthyroidism. As affected individuals are clinically euthyroid and do not require treatment, identification of thyroid hormone transport protein defects is important to avoid unnecessary diagnostic and therapeutic interventions. Mammals share the multilayered system of thyroid hormone binding proteins with humans. Some of them, especially carnivores, do not express TBG. In dogs, this defect has been shown to be caused by a defective hepatocyte nuclear factor-1 binding site in the TBG promoter, preventing TBG synthesis in the liver. The major endogenous thyroid hormone metabolite 3-iodothyronamine (3-T1AM) exerts marked cryogenic, metabolic, cardiac and central nervous system actions. It is bound to apolipoproteinB-100 (ApoB100), possibly facilitating its cellular uptake via interaction with the low density lipoprotein-receptor. This review summarizes the handling of hydrophobic charged thyroid hormone signaling molecules and their metabolite 3-T1AM in aqueous body fluids and the advantages and limits of their serum distributor proteins.

Graphical abstract

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LH signaling induced ptgs2a expression is required for ovulation in zebrafish

Publication date: Available online 28 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Haipei Tang, Yun Liu, Jianzhen Li, Gaofei Li, Yu Chen, Yike Yin, Yin Guo, Christopher H.K. Cheng, Xiaochun Liu, Haoran Lin
It is well known that ovulation is induced by luteinizing hormone (LH) surge. However, the down-stream factors that mediating LH surge induced ovulation are less clear. The cyclooxygenases (also known as PTGS) as key enzymes for prostaglandins synthesis appear to be important for ovulation in mammals, but their functional roles and molecular mechanism in regulation of fish ovulation are largely unexplored. In this study, we have systematically investigated the expression, regulation and functional roles of cox genes during zebrafish ovulation. Three types of cox genes including ptgs1, ptgs2a and ptgs2b have been identified in zebrafish. The ptgs2a was dominantly expressed in the ovary with a maximal level at the maturation stage of the follicles. In addition, the ptgs2a expression is up-regulated by LH signaling in vitro and in vivo. Moreover, co-injection of a selective Ptgs2 inhibitor and non-selective Ptgs inhibitor with hCG could significantly block the stimulatory effect of hCG induced ovulation in vivo. Collectively, our findings indicate that LH signaling induced ptgs2a expression is required for ovulation in zebrafish.



http://ift.tt/2llWEpT

Title: A resistance to thyroid hormone syndrome mutant operates through the target gene repertoire of the wild-type thyroid hormone receptor.

Publication date: Available online 28 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Robyn Jimenez, Martin L. Privalsky
Thyroid hormone receptors (TRs) play crucial roles in vertebrates. Wild-type (WT) TRs function primarily as hormone-regulated transcription factors. A human endocrine disease, Resistance to Thyroid Hormone (RTH)-Syndrome, is caused by inheritance of mutant TRs impaired in the proper regulation of target gene expression. To better understand the molecular basis of RTH we compared the target genes regulated by an RTH-TRβ1 mutant (R429Q) to those regulated by WT-TRβ1. With only a few potential exceptions, the vast majority of genes we were able to identify as regulated by the WT-TRβ1, positively or negatively, were also regulated by the RTH-TRβ1 mutant. We conclude that the actions of R429Q-TRβ1 in RTH-Syndrome most likely reflect the reduced hormone affinity observed for this mutant rather than an alteration in target gene repertoire. Our results highlight the importance of target gene specificity in defining the disease phenotype and improve our understanding of how clinical treatments impact RTH-Syndrome.



http://ift.tt/2l9fKV0

Recent advances on bisphenol-A and endocrine disruptor effects on human prostate cancer

Publication date: Available online 28 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Marzia Di Donato, Gustavo Cernera, Pia Giovannelli, Giovanni Galasso, Antonio Bilancio, Antimo Migliaccio, Gabriella Castoria
Endocrine disrupting chemicals (EDCs) are man-made substances widespread in the environment that include, among many others, bisphenol A (BPA), organochlorinated pesticides and hormone derivatives detectable in meat from animals raised in concentrated animal feeding operations. Increasing evidence indicates that EDCs have a negative impact on human health as well as on male and female fertility. They may also be associated with some endocrine diseases and increased incidence of breast and prostate cancer. This review aims to summarize available data on the (potential) impact of some common EDCs, focusing particularly on BPA, prostate cancer and their mechanisms of action. These compounds interfere with normal hormone signal pathway transduction, resulting in prolonged exposure of receptors to stimuli or interference with cellular hormone signaling in target cells. Understanding the effects of BPA and other EDCs as well as their molecular mechanism(s) may be useful in sensitizing the scientific community and the manufacturing industry to the importance of finding alternatives to their indiscriminate use.



http://ift.tt/2llVQRX

Structural aspects of vitamin D endocrinology

Publication date: Available online 28 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Natacha Rochel, Ferdinand Molnár
1α,25-Dihydroxvitamin D3 (1,25(OH)2D3) is the hormonally active form of vitamin D3. Its synthesis and its metabolites, their transport and elimination as well as action on transcriptional regulation involves the harmonic cooperation of diverse proteins with vitamin D binding capacities such as vitamin D binding protein (DBP), cytochrome P450 enzymes or the nuclear vitamin receptor (VDR). The genomic mechanism of 1,25(OH)2D3 action involves its binding to VDR that functionally acts as a heterodimer with retinoid X receptor. The crystal structures of the most important proteins for vitamin D3, VDR, DBP, CYP2R1 and CYP24A1, have provided identification of mechanisms of actions of these proteins and those mediating VDR-regulated transcription. This review will present the structural information on recognition of the vitamin D3 and metabolites by CYP proteins and DBP as well as the structural basis of VDR activation by 1,25(OH)2D3 and metabolites. Additionally, we will describe, the implications of the VDR mutants associated with hereditary vitamin D-resistant rickets (HVDRR) that display impaired function.



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A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma

Lessons Learned.

The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.

The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.

Background.

Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.

Methods.

Patients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.

Results.

In total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow-up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.

Conclusion.

The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC. The Oncologist 2017;00:1–10

http://ift.tt/2l8Zwel

A Phase II Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab or Placebo in Combination with Gemcitabine for the First-Line Treatment of Pancreatic Adenocarcinoma

Lessons Learned.

The safety profile in the gemcitabine/simtuzumab group was similar to that in the gemcitabine/placebo group.

The addition of simtuzumab to gemcitabine does not improve clinical outcomes in patients with metastatic pancreatic adenocarcinoma

Background.

The humanized IgG4 monoclonal antibody simtuzumab inhibits the extracellular matrix-remodeling enzyme lysyl oxidase-like 2 maintaining pathological stroma in tumors.

Methods.

Adult patients with metastatic pancreatic adenocarcinoma (mPaCa) were randomly assigned to receive intravenous gemcitabine, 1,000 mg/m², in combination with 200 or 700 mg simtuzumab or placebo. Primary endpoint was progression-free survival (PFS), secondary endpoints included overall survival (OS), objective response rate (ORR), and safety.

Results.

Of 240 patients, 80 were randomly assigned to gemcitabine/simtuzumab 700 mg, 79 to gemcitabine/simtuzumab 200 mg, and 81 to gemcitabine/placebo. After a median follow-up of 3.0, 1.9, and 3.4 months for gemcitabine/simtuzumab 700 mg, gemcitabine/simtuzumab 200 mg, and gemcitabine/placebo, respectively, the median PFS was 3.7 months (adjusted hazard ratio [HR], 95% confidence interval [CI], p value vs placebo: 1.09 [0.74–1.61]; p = .73), 3.5 months (1.13 [0.76–1.66], p = .61]), and 3.7 months, respectively. Median OS was 7.6 months (0.83 [0.57–1.22]; p = .28), 5.9 months (1.07 [0.73–1.55]; p = .69), and 5.7 months, respectively. ORRs were 13.9%, 14.5%, and 23.5%, respectively. Simtuzumab was well tolerated.

Conclusions.

The addition of simtuzumab to gemcitabine did not improve clinical outcomes in patients with mPaCa. The Oncologist 2017;00:1–9

http://ift.tt/2lTIlLa

First-line screening tests for Cushing’s syndrome in patients with adrenal incidentaloma: the role of urinary free cortisol measured by LC-MS/MS

Abstract

Introduction and aim

Patients with adrenal incidentaloma present a wide range of cortisol secretion, which is not always properly defined by first-line screening tests recommended to rule out Cushing's syndrome (CS), such as 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), or 24-h urinary free cortisol (UFC). Therefore, we examined the diagnostic performance of each screening test in patients with adrenal incidentaloma.

Materials and methods

In a series of 164 consecutive patients with adrenal incidentaloma, we measured serum cortisol after 1-mg DST, LNSC, and UFC (with LC-MS/MS). Medical history was investigated for cardiovascular events (CVE) in a subgroup of 93 patients with at least 2 years of follow-up.

Results

Serum cortisol <50 nmol/L after 1-mg DST presented the highest sensitivity (100%) to rule out CS, despite a low specificity (62%). UFC > 170 nmol/24 h achieved the highest diagnostic accuracy (sensitivity 98%, specificity 91%, and negative/positive likelihood ratios of 0.02/10.83, respectively). The prevalence of CVE was higher in patients with non-suppressed cortisol after 1-mg DST and high UFC levels (p = 0.018). Traditional cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, BMI > 30 kg/m², smoke or high gender-based waist circumference) were not associated with CVE.

Conclusions

The 1-mg DST at its lowest threshold presented high sensitivity in identifying CS, but its low specificity encourages us to consider UFC levels, measured with LC-MS/MS, to reduce false-positive test results. High UFC levels could also be considered as markers to stratify cardiovascular risk in patients with adrenal incidentaloma.

http://ift.tt/2l8Rh1O

Metabolic Syndrome Negatively Impacts the Outcome of Localized Renal Cell Carcinoma

Abstract

The aim of this study was to analyze the impact of metabolic syndrome (MetS) on outcome of patients with localized renal cell carcinoma (RCC). A retrospective database was compiled consisting of 646 patients who underwent surgery for localized RCC between 2005 and 2014. A total of 439 patients were eligible for final analysis. For diagnosis of MetS, the WHO criteria of 1998 were used. Median follow-up was 32 months (ranging from 2 to 119). Kaplan-Meier and log-rank analyses were performed to compare patients with and without MetS or its components. Univariate and multivariate logistic regression identified prognostic factors for progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). In our cohort, 9.8% (n = 43) of patients were diagnosed with MetS. There were no differences between patients with and without MetS regarding clinicopathological parameters with the exception of patients' age (p = 0.002). Kaplan-Meier and log-rank analyses revealed a shorter PFS for patients with MetS (p = 0.018), whereas no differences were found for each of the single components of MetS, namely, diabetes mellitus (DM) (p = 0.332), BMI >30 kg/m² (p = 0.753), hypertension (p = 0.451), and hypertriglyceridemia (p = 0.891). Logistic regression identified age (HR = 1.92, p = 0.03), tumor stage (HR = 4.37, p < 0.001), grading (HR = 4.57, p < 0.001), nodal status (HR = 3.73, p = 0.04), surgical margin (HR = 1.96, p = 0.04), concomitant sarcomatoid differentiation (HR = 5.06, p < 0.001), and MetS (HR = 1.98, p = 0.04) as independent factors for PFS. For CSS, only age (HR = 2.62, p = 0.035), tumor stage (HR = 3.06, p < 0.02), and grading (HR = 6.83, p < 0.001) were significant. In conclusion, patients with localized RCC and MetS show significantly reduced PFS and might profit from specific consultation and follow-up.

http://ift.tt/2m4jLZV

Review and Management of Acneiform Eruptions in Patients with Immune Disorders

Abstract

Immune disorders are associated with acne or acneiform lesions secondary to the occurrence of acne vulgaris or acneiform eruptions arising as a result of immunosuppressive medication or infection. In this review, we aim to provide an overview of acne and acneiform eruptions that can arise in the immunosuppressed host. Tips for differentiating between various acneiform entities are discussed, as well as a brief overview of treatment considerations.

http://ift.tt/2m4PaeV

Bullous Pemphigoid: A Review of its Diagnosis, Associations and Treatment

Abstract

Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease in Western countries, and typically affects the elderly. BP is immunologically characterized by tissue-bound and circulating autoantibodies directed against either the BP antigen 180 (BP180, or BPAG2) or the BP antigen 230 (BP230, or BPAG1e), or even both, which are components of hemidesmosomes involved in the dermal–epidermal cohesion. Risk factors for BP include old age, neurologic diseases (dementia, Parkinson's disease, cerebrovascular disease), and some particular drugs, including loop diuretics, spironolactone and neuroleptics. The spectrum of clinical presentations is extremely broad. Clinically, BP is an intensely pruritic erythematous eruption with widespread blister formation. In the early stages, or in atypical, non-bullous variants of the disease, only excoriated, eczematous or urticarial lesions (either localized or generalized) are present. The diagnosis of BP relies on immunopathologic findings, especially based on both direct and indirect immunofluorescence microscopy observations, as well as on anti-BP180/BP230 enzyme-linked immunosorbent assays (ELISAs). BP is usually a chronic disease, with spontaneous exacerbations and remissions, which may be accompanied by significant morbidity. In the past decade, potent topical corticosteroids have emerged as an effective and safe first-line treatment for BP, but their long-term feasibility is still controversial. Newer therapeutic agents targeting molecules involved in the inflammatory cascade associated with BP represent future alternatives to classical immunosuppressant drugs for maintenance therapy.

http://ift.tt/2mC65TQ

Black Hairy Tongue: Predisposing Factors, Diagnosis, and Treatment

Abstract

Black hairy tongue (BHT) is a benign condition commonly found among people who smoke, have poor oral hygiene, are immunocompromised, or have a medical condition limiting their ability to practice good oral hygiene. Though this condition is harmless, patients need to be educated on etiology as many common medications are associated with this condition. Patients being placed on certain antibiotics or antipsychotics should be educated on the importance of good oral hygiene or cessation of habits that promote BHT. Similarly, those with medical conditions increasing the risk for the development of BHT should schedule routine visits with their dentist or dental hygienist. Prognosis is good, and treatment consists of gentle brushing of the tongue, but many anecdotal reports exist demonstrating the use of medications or other products to treat this condition. This review addresses the epidemiology, clinical presentation, pathophysiology, etiology, histology, differential diagnosis, and treatment of BHT and lists all of the medications reported to cause this condition.

http://ift.tt/2m4N7rh

Identification of spirobisnaphthalene derivatives with anti-tumor activities from the endophytic fungus Rhytidhysteron rufulum AS21B

Publication date: Available online 27 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Ittipon Siridechakorn, Zongwei Yue, Yanisa Mittraphab, Xiaoguang Lei, Khanitha Pudhom
The cultivation of the mangrove-derived fungus Rhytidhysteron rufulum AS21B in acidic condition changed its secondary metabolite profile. Investigation of the culture broth extract led to the isolation and identification of two new spirobisnaphthalenes (1 and 2) together with eleven known compounds (3–13) from the crude extract of the fungus grown under an acidic condition as well as six known compounds (4, 10, 14-17) were isolated from the crude extract of the fungus grown under an neutral condition. Their structures were elucidated on the basis of extensive spectroscopic data. The isolated compounds were evaluated for their cytotoxicity against two human cancer cell lines, Ramos lymphoma and drug resistant NSCLC H1975. Compounds 2 and 10 displayed the most promising anti-tumor activity against both cancer cell lines.

Graphical abstract

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Development of α1,6-fucosyltransferase inhibitors through the diversity-oriented syntheses of GDP-fucose mimics using the coupling between alkyne and sulfonyl azide

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yoshiyuki Manabe, Satomi Kasahara, Yohei Takakura, Xiaoxiao Yang, Shinji Takamatsu, Yoshihiro Kamada, Eiji Miyoshi, Daisuke Yoshidome, Koichi Fukase
We developed α 1,6-fucosyltransferase (FUT8) inhibitors through a diversity-oriented synthesis. The coupling reaction between the fucose unit containing alkyne and the guanine unit containing sulfonyl azide under various conditions afforded a series of Guanosine 5′-diphospho-β-L-fucose (GDP-fucose) analogs. The synthesized compounds displayed FUT8 inhibition activity. A docking study revealed that the binding mode of the inhibitor synthesized with FUT8 was similar to that of GDP-fucose.

Graphical abstract

http://ift.tt/2ma4181

Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Elvar Örn Viktorsson, Bendik Melling Grøthe, Reidun Aesoy, Misbah Sabir, Simen Snellingen, Anthony Prandina, Ove Alexander Høgmoen Åstrand, Tore Bonge-Hansen, Stein Ove Døskeland, Lars Herfindal, Pål Rongved
A new efficient total synthesis of the phenazine 5,10-dioxide natural products iodinin and myxin and new compounds derived from them was achieved in few steps, a key-step being 1,6-dihydroxyphenazine di-N-oxidation. Analogues prepared from iodinin, including myxin and 2-ethoxy-2-oxoethoxy derivatives, had fully retained cytotoxic effect against human cancer cells (MOLM-13 leukemia) at atmospheric and low oxygen level. Moreover, iodinin was for the first time shown to be hypoxia selective. The structure-activity relationship for leukemia cell death induction revealed that the level of N-oxide functionality was essential for cytotoxicity. It also revealed that only one of the two phenolic functions is required for activity, allowing the other one to be modified without loss of potency.

Graphical abstract

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Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation

Publication date: Available online 27 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Tomoko Ogiyama, Mitsuhiro Yamaguchi, Nobuya Kurikawa, Shoko Honzumi, Yamamoto Yuka, Daisuke Sugiyama, Hideo Takakusa, Shinichi Inoue
Hormone sensitive lipase (HSL) has emerged as an attractive target for the treatment of dyslipidemia. We previously reported compound 1 as a potent and orally active HSL inhibitor. Although an attractive profile was demonstrated, subsequent studies revealed that compound 1 has a bioactivation liability. The oxygen-carbon linker in compound 1 was identified as being potentially responsible for reactive metabolite formation. By exchanging of this susceptible fragment was feasible, and a benzanilide derivative 6b with a decreased bioactivation liability was obtained. Further modification of the novel benzanilide scaffold resulted in the identification of compound 24b. Compound 24b exhibited potent HSL inhibitory activity (IC50 = 2 nM) with a significantly reduced bioactivation potential. Oral administration of compound 24b exhibited an antilipolytic effect on rats at 3 mg/kg.

Graphical abstract

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Design, synthesis, and biological evaluation of a highly water-soluble psoralen-based photosensitizer

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yoshiyuki Uruma, Takuya Nonomura, Priscilla Yoong Mei Yen, Marie Edatani, Ryotaro Yamamoto, Kunishige Onuma, Futoshi Okada
In recent years, photodynamic therapy (PDT) has been approved for treating various medical conditions, including cancer. PDT is a treatment that employs a particular drugs, called photosensitizers which work along with specific light source. The growth of this medical industry is expanding as it is another promising alternative to treat cancer which lessen the burden of treatments in patients. This includes the benefits of minimally invasive procedures and delivering high accuracy in targeting mutations. In recent two decades, cancer researchers have produced remarkable studies on developing photosensitizers that enhance understanding of biology and genetics of cancer. It is unfortunate that not all PDT can work as well as other profound treatment because PDT has various limitations like PDT leads photosensitivity reaction that arises when the photosensitizer remains in the body for a long period of time. In this paper, our studies centers on synthesizing a highly soluble photosensitizing agent with improved effectiveness on detecting cancer cells.

Graphical abstract

http://ift.tt/2mag2dN

Enhancing Polo-like Kinase 1 Selectivity of Polo-box Domain-binding Peptides

Publication date: Available online 28 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Xue Zhi Zhao, David Hymel, Terrence R. Burke
An important goal in the development of polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors is selectivity for Plk1 relative to Plk2 and Plk3. In our current work we show that Plk1 PBD selectivity can be significantly enhanced by modulating interactions within a previously discovered "cryptic pocket" and a more recently identified proximal "auxiliary pocket."

Graphical abstract

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Rational design and studies of excimer forming novel dual probes to target RNA

Publication date: Available online 27 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): O.A. Krasheninina, A.A. Lomzov, V.S. Fishman, D.S. Novopashina, A.G. Venyaminova
In this paper, we report structure-based rational design and physico-chemical and biological studies of novel pyrene excimer forming dual probes for visualization of intracellular RNAs. Herein, the probes based on 2'-O-methyl RNA with linkers of different structure and length between pyrene moiety and ribose are studied with respect to their hybridization and spectral properties. We found optimal linkers that provide more intense excimer emission (at ∼480 nm) of RNA-bound probes; particularly, the length of the linker arm of the 3'-component of dual probes plays a key role in formation of pyrene excimer. Calculated molecular dynamics trajectories and probability distributions of pyrene-pyrene dimer formation upon hybridization of the dual probes with RNA target are in agreement with the obtained fluorescence spectroscopy data for the corresponding duplexes. Our study demonstrates the excellent binding properties of new dual probes to structured RNA and their feasibility for the visualization of intracellular RNA targets.

Graphical abstract

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Role of the sugar moiety on the opioid receptor binding and conformation of a series of enkephalin neoglycopeptides

Publication date: Available online 27 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Mònica Rosa, Verónica Gonzalez-Nunez, Katherine Barreto-Valer, Filipa Marcelo, Julia Sánchez-Sánchez, Luis P. Calle, Juan C. Arévalo, Raquel E. Rodríguez, Jesús Jiménez Barbero, Gemma Arsequell, Gregorio Valencia
Glycosylation by simple sugars is a drug discovery alternative that has been explored with varying success for enhancing the potency and bioavailability of opioid peptides. Long ago we described two O-glycosides having either β-Glucose and β-Galactose of (D-Met²,Pro⁵)-enkephalinamide showing one of the highest antinociceptive activities known. Here, we report the resynthesis of these two analogs and the preparation of three novel neoglycopeptide derivatives (α-Mannose, β-Lactose and β-Cellobiose). Binding studies to cloned zebrafish opioid receptors showed very small differences of affinity between the parent compound and the five glycopeptides thus suggesting that the nature of the carbohydrate moiety plays a minor role in determining the binding mode. Indeed, NMR conformational studies, combined with molecular mechanics calculations, indicated that all glycopeptides present the same major conformation either in solution or membrane-like environment. The evidences provided here highlight the relevance for in vivo activity of the conjugating bond between the peptide and sugar moieties in opioid glycopeptides.

Graphical abstract

http://ift.tt/2magSqY