Pharmaceuticals

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Open AccessArticle

A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice

by Giovanni Pellegrini, Klaudia Siwowska, Stephanie Haller, Daniel J. Antoine, Roger Schibli, Anja Kipar and Cristina Müller

Pharmaceuticals 2017, 10(2), 57; https://doi.org/10.3390/ph10020057 - 21 Jun 2017

Cited by 12 | Viewed by 5265

Abstract

Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge [...] Read more.

Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that—in this case—cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of ¹⁷⁷Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of γ-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same ¹⁷⁷Lu-folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage. Full article

(This article belongs to the Special Issue Emerging Theranostic Tracers in the Context of Radiopharmaceutical Drug Development)

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Open AccessArticle

Exploring Wound-Healing Genomic Machinery with a Network-Based Approach

by Francesca Vitali, Simone Marini, Martina Balli, Hanne Grosemans, Maurilio Sampaolesi, Yves A. Lussier, Maria Gabriella Cusella De Angelis and Riccardo Bellazzi

Pharmaceuticals 2017, 10(2), 55; https://doi.org/10.3390/ph10020055 - 21 Jun 2017

Cited by 6 | Viewed by 6047

Abstract

The molecular mechanisms underlying tissue regeneration and wound healing are still poorly understood despite their importance. In this paper we develop a bioinformatics approach, combining biology and network theory to drive experiments for better understanding the genetic underpinnings of wound healing mechanisms and [...] Read more.

The molecular mechanisms underlying tissue regeneration and wound healing are still poorly understood despite their importance. In this paper we develop a bioinformatics approach, combining biology and network theory to drive experiments for better understanding the genetic underpinnings of wound healing mechanisms and for selecting potential drug targets. We start by selecting literature-relevant genes in murine wound healing, and inferring from them a Protein-Protein Interaction (PPI) network. Then, we analyze the network to rank wound healing-related genes according to their topological properties. Lastly, we perform a procedure for in-silico simulation of a treatment action in a biological pathway. The findings obtained by applying the developed pipeline, including gene expression analysis, confirms how a network-based bioinformatics method is able to prioritize candidate genes for in vitro analysis, thus speeding up the understanding of molecular mechanisms and supporting the discovery of potential drug targets. Full article

(This article belongs to the Special Issue Tissue-Protective Agents: New Drugs and Technologies)

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Open AccessArticle

The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair ⁸⁶Y and ⁹⁰Y

by Frank Rösch, Hans Herzog and Syed M. Qaim

Pharmaceuticals 2017, 10(2), 56; https://doi.org/10.3390/ph10020056 - 20 Jun 2017

Cited by 114 | Viewed by 12738

Abstract

In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The [...] Read more.

In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the “best one” for that individual patient. Transforming diagnostic imaging into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. This theranostic approach in nuclear medicine is traced back to the first use of the radionuclide pair ⁸⁶Y/⁹⁰Y, which allowed a combination of PET and internal radiotherapy. Whereas the β-emitting therapeutic radionuclide ⁹⁰Y (t½ = 2.7 d) had been available for a long time via the ⁹⁰Sr/⁹⁰Y generator system, the β⁺ emitter ⁸⁶Y (t½ = 14.7 h) had to be developed for medical application. A brief outline of the various aspects of radiochemical and nuclear development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel, the paper discusses the methodology introduced to quantify molecular imaging of ⁸⁶Y-labelled compounds in terms of multiple and long-term PET recordings. It highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue ⁹⁰Y-labelled compound in terms of mGy or mSv per MBq ⁹⁰Y injected. Finally, the current and possible future development of theranostic approaches based on different PET and therapy nuclides is discussed. Full article

(This article belongs to the Special Issue Emerging Theranostic Tracers in the Context of Radiopharmaceutical Drug Development)

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Open AccessReview

The Good the Bad and the Ugly of Glycosaminoglycans in Tissue Engineering Applications

by Bethanie I. Ayerst, Catherine L.R. Merry and Anthony J. Day

Pharmaceuticals 2017, 10(2), 54; https://doi.org/10.3390/ph10020054 - 13 Jun 2017

Cited by 33 | Viewed by 9108

Abstract

High sulfation, low cost, and the status of heparin as an already FDA- and EMA- approved product, mean that its inclusion in tissue engineering (TE) strategies is becoming increasingly popular. However, the use of heparin may represent a naïve approach. This is because [...] Read more.

High sulfation, low cost, and the status of heparin as an already FDA- and EMA- approved product, mean that its inclusion in tissue engineering (TE) strategies is becoming increasingly popular. However, the use of heparin may represent a naïve approach. This is because tissue formation is a highly orchestrated process, involving the temporal expression of numerous growth factors and complex signaling networks. While heparin may enhance the retention and activity of certain growth factors under particular conditions, its binding ‘promiscuity’ means that it may also inhibit other factors that, for example, play an important role in tissue maintenance and repair. Within this review we focus on articular cartilage, highlighting the complexities and highly regulated processes that are involved in its formation, and the challenges that exist in trying to effectively engineer this tissue. Here we discuss the opportunities that glycosaminoglycans (GAGs) may provide in advancing this important area of regenerative medicine, placing emphasis on the need to move away from the common use of heparin, and instead focus research towards the utility of specific GAG preparations that are able to modulate the activity of growth factors in a more controlled and defined manner, with less off-target effects. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Proteoglycans)

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Open AccessArticle

In Vitro and In Vivo Studies of Alar-Nasal Cartilage Using Autologous Micro-Grafts: The Use of the Rigenera^® Protocol in the Treatment of an Osteochondral Lesion of the Nose

by Gabriele Ceccarelli, Pietro Gentile, Marco Marcarelli, Martina Balli, Flavio Lorenzo Ronzoni, Laura Benedetti and Maria Gabriella Cusella De Angelis

Pharmaceuticals 2017, 10(2), 53; https://doi.org/10.3390/ph10020053 - 13 Jun 2017

Cited by 27 | Viewed by 7123

Abstract

Cartilage defects represent a serious problem due to the poor regenerative properties of this tissue. Regarding the nose, nasal valve collapse is associated with nasal blockage and persistent airway obstruction associated with a significant drop in the quality of life for patients. In [...] Read more.

Cartilage defects represent a serious problem due to the poor regenerative properties of this tissue. Regarding the nose, nasal valve collapse is associated with nasal blockage and persistent airway obstruction associated with a significant drop in the quality of life for patients. In addition to surgical techniques, several cell-based tissue-engineering strategies are studied to improve cartilage support in the nasal wall, that is, to ameliorate wall insufficiency. Nevertheless, there are no congruent data available on the benefit for patients during the follow-up time. In this manuscript, we propose an innovative approach in the treatment of cartilage defects in the nose (nasal valve collapse) based on autologous micro-grafts obtained by mechanical disaggregation of a small portion of cartilage tissue (Rigenera^® protocol). In particular, we first analyzed in vitro murine and human cartilage micro-grafts; secondly, we analyzed the clinical results of a patient with pinched nose deformity treated with autologous micro-grafts of chondrocytes obtained by Rigenera^® protocol. The use of autologous micro-graft produced promising results in surgery treatment of cartilage injuries and could be safely and easily administrated to patients with cartilage tissue defects. Full article

(This article belongs to the Special Issue Tissue-Protective Agents: New Drugs and Technologies)

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Open AccessArticle

Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure–Activity Relationship (HQSAR) Modeling of Amino–Imino Tautomers

by Marcelle L. F. Bispo, Camilo H. S. Lima, Laura N. F. Cardoso, André L. P. Candéa, Flávio A. F. M. Bezerra, Maria C. S. Lourenço, Maria G. M. O. Henriques, Ricardo B. Alencastro, Carlos R. Kaiser, Marcus V. N. Souza and Magaly G. Albuquerque

Pharmaceuticals 2017, 10(2), 52; https://doi.org/10.3390/ph10020052 - 9 Jun 2017

Cited by 4 | Viewed by 5761

Abstract

In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations [...] Read more.

In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01–D21). Considering the active compounds of series A (A01–A13), B (B01–B13), C (C01–C07), and D (D01–D09), we compose a data set of 42 compounds and carried out hologram quantitative structure–activity relationship (HQSAR) analysis. The amino–imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SE_cv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SE_cv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity. Full article

(This article belongs to the Special Issue Chemoinformatics and Drug Design)

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Open AccessReview

Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds

by Guilherme Felipe dos Santos Fernandes, Chung Man Chin and Jean Leandro Dos Santos

Pharmaceuticals 2017, 10(2), 51; https://doi.org/10.3390/ph10020051 - 1 Jun 2017

Cited by 39 | Viewed by 8362

Abstract

Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and [...] Read more.

Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed. Full article

(This article belongs to the Special Issue Selected Papers from the 2nd International Electronic Conference on Medicinal Chemistry)

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Open AccessArticle

Chiral Derivatives of Xanthones: Investigation of the Effect of Enantioselectivity on Inhibition of Cyclooxygenases (COX-1 and COX-2) and Binding Interaction with Human Serum Albumin

by Carla Fernandes, Andreia Palmeira, Inês I. Ramos, Carlos Carneiro, Carlos Afonso, Maria Elizabeth Tiritan, Honorina Cidade, Paula C.A.G. Pinto, M. Lúcia M.F.S. Saraiva, Salette Reis and Madalena M.M. Pinto

Pharmaceuticals 2017, 10(2), 50; https://doi.org/10.3390/ph10020050 - 31 May 2017

Cited by 26 | Viewed by 7631

Abstract

Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and [...] Read more.

Searching of new enantiomerically pure chiral derivatives of xanthones (CDXs) with potential pharmacological properties, particularly those with anti-inflammatory activity, has remained an area of interest of our group. Herein, we describe in silico studies and in vitro inhibitory assays of cyclooxygenases (COX-1 and COX-2) for different enantiomeric pairs of CDXs. The evaluation of the inhibitory activities was performed by using the COX Inhibitor Screening Assay Kit. Docking simulations between the small molecules (CDXs; known ligands and decoys) and the enzyme targets were undertaken with AutoDock Vina embedded in PyRx—Virtual Screening Tool software. All the CDXs evaluated exhibited COX-1 and COX-2 inhibition potential as predicted. Considering that the (S)-(−)-enantiomer of the nonsteroidal anti-inflammatory drug ketoprofen preferentially binds to albumin, resulting in lower free plasma concentration than (R)-(+)-enantiomer, protein binding affinity for CDXs was also evaluated by spectrofluorimetry as well as in in silico. For some CDXs enantioselectivity was observed. Full article

(This article belongs to the Special Issue Selected Papers from the 2nd International Electronic Conference on Medicinal Chemistry)

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Open AccessArticle

Syntheses of Radioiodinated Pyrimidine-2,4,6-Triones as Potential Agents for Non-Invasive Imaging of Matrix Metalloproteinases

by Hans-Jörg Breyholz, Klaus Kopka, Michael Schäfers and Stefan Wagner

Pharmaceuticals 2017, 10(2), 49; https://doi.org/10.3390/ph10020049 - 30 May 2017

Cited by 8 | Viewed by 5284

Abstract

Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of live-threatening diseases. Therefore, MMP imaging for example with radiolabelled MMP inhibitors (MMPIs) potentially represents a valuable tool for clinical diagnostics using non-invasive single photon emission computed tomography (SPECT) or [...] Read more.

Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of live-threatening diseases. Therefore, MMP imaging for example with radiolabelled MMP inhibitors (MMPIs) potentially represents a valuable tool for clinical diagnostics using non-invasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. This work includes the organic chemical syntheses and in vitro evaluation of five iodinated barbiturate based MMPIs and the selection of derivative 9 for radiosyntheses of isotopologues [¹²³I]9 potentially useful for MMP SPECT imaging and [¹²⁴I]9 for MMP PET imaging. Full article

(This article belongs to the Special Issue Emerging Theranostic Tracers in the Context of Radiopharmaceutical Drug Development)

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Open AccessEditorial

Announcing the 2017 Pharmaceuticals Travel Award for Young Post-Doctoral Researchers

by Jean Jacques Vanden Eynde

Pharmaceuticals 2017, 10(2), 48; https://doi.org/10.3390/ph10020048 - 22 May 2017

Cited by 1 | Viewed by 3505

Abstract

Last year, for the ﬁrst time in its history, our Journal was able to offer a travel grant of 800 CHF to a young researcher in the ﬁeld of medicinal chemistry Full article

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Open AccessArticle

Synthesis and Pharmacological Properties of Novel Esters Based on Monoterpenoids and Glycine

by Mariia Nesterkina and Iryna Kravchenko

Pharmaceuticals 2017, 10(2), 47; https://doi.org/10.3390/ph10020047 - 18 May 2017

Cited by 22 | Viewed by 7200

Abstract

Esters based on mono- and bicyclic terpenoids with glycine have been synthesized via Steglich esterification and characterized by ¹H-NMR, IR, and mass spectral studies. Their analgesic and anti-inflammatory activities were investigated after transdermal delivery on models of formalin, capsaicin, and AITC-induced pain, [...] Read more.

Esters based on mono- and bicyclic terpenoids with glycine have been synthesized via Steglich esterification and characterized by ¹H-NMR, IR, and mass spectral studies. Their analgesic and anti-inflammatory activities were investigated after transdermal delivery on models of formalin, capsaicin, and AITC-induced pain, respectively. Glycine esters of menthol and borneol exhibited higher antinociceptive action, whereas eugenol derivative significantly suppressed the development of the inflammatory process. The mechanism of competitive binding between terpenoid esters and TRPA1/TRPV1 agonists was proposed explaining significant analgesic effect of synthesized derivatives. For an explanation of high anti-inflammatory activity, competitive inhibition between terpenoid esters and AITC for binding sites of the TRPA1 ion channel has been suggested. Full article

(This article belongs to the Special Issue Selected Papers from the 2nd International Electronic Conference on Medicinal Chemistry)

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Open AccessReview

PKC in Regenerative Therapy: New Insights for Old Targets

by Marta Rui, Rita Nasti, Emanuele Bignardi, Serena Della Volpe, Giacomo Rossino, Daniela Rossi and Simona Collina

Pharmaceuticals 2017, 10(2), 46; https://doi.org/10.3390/ph10020046 - 18 May 2017

Cited by 5 | Viewed by 6672

Abstract

Effective therapies for chronic or non-healing wounds are still lacking. These tissue insults often result in severe clinical complications (i.e., infections and/or amputation) and sometimes lead to patient death. Accordingly, several research groups have focused their efforts in finding innovative and powerful therapeutic [...] Read more.

Effective therapies for chronic or non-healing wounds are still lacking. These tissue insults often result in severe clinical complications (i.e., infections and/or amputation) and sometimes lead to patient death. Accordingly, several research groups have focused their efforts in finding innovative and powerful therapeutic strategies to overcome these issues. On the basis of these considerations, the comprehension of the molecular cascades behind these pathological conditions could allow the identification of molecules against chronic wounds. In this context, the regulation of the Protein Kinase C (PKC) cascade has gained relevance in the prevention and/or reparation of tissue damages. This class of phosphorylating enzymes has already been considered for different physiological and pathological pathways and modulation of such enzymes may be useful in reparative processes. Herein, the recent developments in this field will be disclosed, highlighting the pivotal role of PKC α and δ in regenerative medicine. Moreover, an overview of well-established PKC ligands, acting via the modulation of these isoenzymes, will be deeply investigated. This study is aimed at re-evaluating widely known PKC modulators, currently utilized for treating other diseases, as fruitful molecules in wound-healing. Full article

(This article belongs to the Special Issue Tissue-Protective Agents: New Drugs and Technologies)

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Open AccessReview

Novel Radiolabeled Bisphosphonates for PET Diagnosis and Endoradiotherapy of Bone Metastases

by Nina Pfannkuchen, Marian Meckel, Ralf Bergmann, Michael Bachmann, Chandrasekhar Bal, Mike Sathekge, Wolfgang Mohnike, Richard P. Baum and Frank Rösch

Pharmaceuticals 2017, 10(2), 45; https://doi.org/10.3390/ph10020045 - 18 May 2017

Cited by 48 | Viewed by 8177

Abstract

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of ^99mTc are predominantly used [...] Read more.

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of ^99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the ⁶⁸Ge/⁶⁸Ga generator, an analog to the established ^99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the β-emitter ¹⁷⁷Lu. This overview describes the possibility of diagnosing bone metastases using [⁶⁸Ga]Ga-BPAMD (⁶⁸Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [¹⁷⁷Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new ⁶⁸Ga- and ¹⁷⁷Lu-labeled bisphosphonates offering improved pharmacological properties. Full article

(This article belongs to the Special Issue Emerging Theranostic Tracers in the Context of Radiopharmaceutical Drug Development)

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Open AccessReview

Pathogenesis and Inhibition of Flaviviruses from a Carbohydrate Perspective

by So Young Kim, Bing Li and Robert J. Linhardt

Pharmaceuticals 2017, 10(2), 44; https://doi.org/10.3390/ph10020044 - 4 May 2017

Cited by 43 | Viewed by 10207

Abstract

Flaviviruses are enveloped, positive single stranded ribonucleic acid (RNA) viruses with various routes of transmission. While the type and severity of symptoms caused by pathogenic flaviviruses vary from hemorrhagic fever to fetal abnormalities, their general mechanism of host cell entry is similar. All [...] Read more.

Flaviviruses are enveloped, positive single stranded ribonucleic acid (RNA) viruses with various routes of transmission. While the type and severity of symptoms caused by pathogenic flaviviruses vary from hemorrhagic fever to fetal abnormalities, their general mechanism of host cell entry is similar. All pathogenic flaviviruses, such as dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, and Zika virus, bind to glycosaminglycans (GAGs) through the putative GAG binding sites within their envelope proteins to gain access to the surface of host cells. GAGs are long, linear, anionic polysaccharides with a repeating disaccharide unit and are involved in many biological processes, such as cellular signaling, cell adhesion, and pathogenesis. Flavivirus envelope proteins are N-glycosylated surface proteins, which interact with C-type lectins, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) through their glycans. In this review, we discuss both host and viral surface receptors that have the carbohydrate components, focusing on the surface interactions in the early stage of flavivirus entry. GAG-flavivirus envelope protein interactions as well as interactions between flavivirus envelope proteins and DC-SIGN are discussed in detail. This review also examines natural and synthetic inhibitors of flaviviruses that are carbohydrate-based or carbohydrate-targeting. Both advantages and drawbacks of these inhibitors are explored, as are potential strategies to improve their efficacy to ultimately help eradicate flavivirus infections. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Proteoglycans)

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Open AccessOpinion

Information Phage Therapy Research Should Report

by Stephen T. Abedon

Pharmaceuticals 2017, 10(2), 43; https://doi.org/10.3390/ph10020043 - 30 Apr 2017

Cited by 58 | Viewed by 8089

Abstract

Bacteriophages, or phages, are viruses which infect bacteria. A large subset of phages infect bactericidally and, consequently, for nearly one hundred years have been employed as antibacterial agents both within and outside of medicine. Clinically these applications are described as phage or bacteriophage [...] Read more.

Bacteriophages, or phages, are viruses which infect bacteria. A large subset of phages infect bactericidally and, consequently, for nearly one hundred years have been employed as antibacterial agents both within and outside of medicine. Clinically these applications are described as phage or bacteriophage therapy. Alternatively, and especially in the treatment of environments, this practice instead may be described as a phage-mediated biocontrol of bacteria. Though the history of phage therapy has involved substantial clinical experimentation, current standards along with drug regulations have placed a premium on preclinical approaches, i.e., animal experiments. As such, it is important for preclinical experiments not only to be held to high standards but also to be reported in a manner which improves translation to clinical utility. Here I address this latter issue, that of optimization of reporting of preclinical as well as clinical experiments. I do this by providing a list of pertinent information and data which, in my opinion, phage therapy experiments ought to present in publications, along with tips for best practices. The goal is to improve the ability of readers to gain relevant information from reports on phage therapy research, to allow other researchers greater potential to repeat or extend findings, to ease transitions from preclinical to clinical development, and otherwise simply to improve phage therapy experiments. Targeted are not just authors but also reviewers, other critical readers, writers of commentaries, and, perhaps, formulators of guidelines or policy. Though emphasizing therapy, many points are applicable to phage-mediated biocontrol of bacteria more generally. Full article

(This article belongs to the Special Issue Phage Therapy and Phage-Mediated Biological Control)

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Open AccessArticle

Glycosaminoglycan Binding and Non-Endocytic Membrane Translocation of Cell-Permeable Octaarginine Monitored by Real-Time In-Cell NMR Spectroscopy

by Yuki Takechi-Haraya, Kenzo Aki, Yumi Tohyama, Yuichi Harano, Toru Kawakami, Hiroyuki Saito and Emiko Okamura

Pharmaceuticals 2017, 10(2), 42; https://doi.org/10.3390/ph10020042 - 15 Apr 2017

Cited by 14 | Viewed by 6234

Abstract

Glycosaminoglycans (GAGs), which are covalently-linked membrane proteins at the cell surface have recently been suggested to involve in not only endocytic cellular uptake but also non-endocytic direct cell membrane translocation of arginine-rich cell-penetrating peptides (CPPs). However, in-situ comprehensive observation and the quantitative analysis [...] Read more.

Glycosaminoglycans (GAGs), which are covalently-linked membrane proteins at the cell surface have recently been suggested to involve in not only endocytic cellular uptake but also non-endocytic direct cell membrane translocation of arginine-rich cell-penetrating peptides (CPPs). However, in-situ comprehensive observation and the quantitative analysis of the direct membrane translocation processes are challenging, and the mechanism therefore remains still unresolved. In this work, real-time in-cell NMR spectroscopy was applied to investigate the direct membrane translocation of octaarginine (R8) into living cells. By introducing 4-trifluoromethyl-l-phenylalanine to the N terminus of R8, the non-endocytic membrane translocation of ¹⁹F-labeled R8 (¹⁹F-R8) into a human myeloid leukemia cell line was observed at 4 °C with a time resolution in the order of minutes. ¹⁹F NMR successfully detected real-time R8 translocation: the binding to anionic GAGs at the cell surface, followed by the penetration into the cell membrane, and the entry into cytosol across the membrane. The NMR concentration analysis enabled quantification of how much of R8 was staying in the respective translocation processes with time in situ. Taken together, our in-cell NMR results provide the physicochemical rationale for spontaneous penetration of CPPs in cell membranes. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Proteoglycans)

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Open AccessArticle

Biotinylated Chlorin and Its Zinc and Indium Complexes: Synthesis and In Vitro Biological Evaluation for Photodynamic Therapy

by Meden F. Isaac-Lam and Dewana M. Hammonds

Pharmaceuticals 2017, 10(2), 41; https://doi.org/10.3390/ph10020041 - 15 Apr 2017

Cited by 18 | Viewed by 4913

Abstract

The synthesis and characterization of biotinylated chlorin photosensitizer and the corresponding zinc and indium complexes are described for potential applications in photodynamic therapy (PDT) for cancer. Phototoxicity of the biotin-chlorin conjugate and the metallated complexes was determined in colon carcinoma CT26 cell lines [...] Read more.

The synthesis and characterization of biotinylated chlorin photosensitizer and the corresponding zinc and indium complexes are described for potential applications in photodynamic therapy (PDT) for cancer. Phototoxicity of the biotin-chlorin conjugate and the metallated complexes was determined in colon carcinoma CT26 cell lines known to overexpress biotin (Vit B₇) receptors. Cell survival assay indicated that the biotinylated chlorin and indium complex showed increased cell growth inhibition than the zinc complex and the starting chlorin (methyl pheophorbide). Fluorescence microcopy studies revealed the generation of apoptotic cells upon light irradiation of colon cells treated with the indium complex. Targeting biotin receptors in cancer cells can improve specificity of photosensitizers for PDT applications. Full article

(This article belongs to the Special Issue Metal-Based Drugs)

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Open AccessReview

Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

by Saurabh Chhabra

Pharmaceuticals 2017, 10(2), 40; https://doi.org/10.3390/ph10020040 - 11 Apr 2017

Cited by 40 | Viewed by 10099

Abstract

The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the [...] Read more.

The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death. The simultaneous inhibition of the proteasome, by proteasome inhibitors (PIs) and the aggresome, by histone deacetylase inhibitors (HDACi) results in a synergistic increase in cytotoxicity in myeloma cell lines. This review provides an overview of mechanisms of action of second-generation PIs and HDACi in multiple myeloma (MM), the clinical results currently observed with these agents and assesses the potential therapeutic impact of the different agents in the two classes. The second-generation PIs offer benefits in terms of increased efficacy, reduced neurotoxicity as off-target effect and may overcome resistance to bortezomib because of their different chemical structure, mechanism of action and biological properties. HDACi with anti-myeloma activity in clinical development discussed in this review include vorinostat, panobinostat and selective HDAC6 inhibitor, ricolinostat. Full article

(This article belongs to the Special Issue New Drugs in Hematology)

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Open AccessReview

Role of TRPM7 in Cancer: Potential as Molecular Biomarker and Therapeutic Target

by Nelson S. Yee

Pharmaceuticals 2017, 10(2), 39; https://doi.org/10.3390/ph10020039 - 5 Apr 2017

Cited by 71 | Viewed by 9075

Abstract

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed ion channel with intrinsic kinase activity. Molecular and electrophysiological analyses of the structure and activity of TRPM7 have revealed functional coupling of its channel and kinase activity. Studies have indicated the [...] Read more.

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed ion channel with intrinsic kinase activity. Molecular and electrophysiological analyses of the structure and activity of TRPM7 have revealed functional coupling of its channel and kinase activity. Studies have indicated the important roles of TRPM7 channel-kinase in fundamental cellular processes, physiological responses, and embryonic development. Accumulating evidence has shown that TRPM7 is aberrantly expressed and/or activated in human diseases including cancer. TRPM7 plays a variety of functional roles in cancer cells including survival, cell cycle progression, proliferation, growth, migration, invasion, and epithelial-mesenchymal transition (EMT). Data from a study using mouse xenograft of human cancer show that TRPM7 is required for tumor growth and metastasis. The aberrant expression of TRPM7 and its genetic mutations/polymorphisms have been identified in various types of carcinoma. Chemical modulators of TRPM7 channel produced inhibition of proliferation, growth, migration, invasion, invadosome formation, and markers of EMT in cancer cells. Taken together, these studies suggest the potential value of exploiting TRPM7 channel-kinase as a molecular biomarker and therapeutic target in human malignancies. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels in Drug Discovery: Old Concepts & New Thoughts)

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Open AccessArticle

Systematic Analysis of Pharmaceutical Preparations of Chondroitin Sulfate Combined with Glucosamine

by Gustavo R.C. Santos, Adriana A. Piquet, Bianca F. Glauser, Ana M.F. Tovar, Mariana S. Pereira, Eduardo Vilanova and Paulo A.S. Mourão

Pharmaceuticals 2017, 10(2), 38; https://doi.org/10.3390/ph10020038 - 1 Apr 2017

Cited by 26 | Viewed by 10569

Abstract

Glycosaminoglycans are carbohydrate-based compounds widely employed as nutraceuticals or prescribed drugs. Oral formulations of chondroitin sulfate combined with glucosamine sulfate have been increasingly used to treat the symptoms of osteoarthritis and osteoarthrosis. The chondroitin sulfate of these combinations can be obtained from shark [...] Read more.

Glycosaminoglycans are carbohydrate-based compounds widely employed as nutraceuticals or prescribed drugs. Oral formulations of chondroitin sulfate combined with glucosamine sulfate have been increasingly used to treat the symptoms of osteoarthritis and osteoarthrosis. The chondroitin sulfate of these combinations can be obtained from shark or bovine cartilages and hence presents differences regarding the proportions of 4- and 6-sulfated N-acetyl β-d-galactosamine units. Herein, we proposed a systematic protocol to assess pharmaceutical batches of this combination drug. Chemical analyses on the amounts of chondroitin sulfate and glucosamine in the batches were in accordance with those declared by the manufacturers. Anion-exchange chromatography has proven more effective than electrophoresis to determine the type of chondroitin sulfate present in the combinations and to detect the presence of keratan sulfate, a common contaminant found in batches prepared with shark chondroitin sulfate. 1D NMR spectra revealed the presence of non-sulfated instead of sulfated glucosamine in the formulations and thus in disagreement with the claims declared on the label. Moreover, 1D and 2D NMR analyses allowed a precise determination on the chemical structures of the chondroitin sulfate present in the formulations. The set of analytical tools suggested here could be useful as guidelines to improve the quality of this medication. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Proteoglycans)

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Open AccessReview

Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine

by Andy D. Weyer and Sonya G. Lehto

Pharmaceuticals 2017, 10(2), 37; https://doi.org/10.3390/ph10020037 - 30 Mar 2017

Cited by 70 | Viewed by 7193

Abstract

A review. Development of pharmaceutical antagonists of transient receptor potential melastatin 8 (TRPM8) have been pursued for the treatment of chronic pain and migraine. This review focuses on the current state of this progress. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels in Drug Discovery: Old Concepts & New Thoughts)

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Open AccessArticle

Development of a Glycosaminoglycan Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial Cell Dysfunction

by James R. Wodicka, Andrea M. Chambers, Gurneet S. Sangha, Craig J. Goergen and Alyssa Panitch

Pharmaceuticals 2017, 10(2), 36; https://doi.org/10.3390/ph10020036 - 29 Mar 2017

Cited by 17 | Viewed by 6474

Abstract

Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases [...] Read more.

Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived, selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT, treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Proteoglycans)

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Open AccessReview

Modulation of TRP Channel Activity by Hydroxylation and Its Therapeutic Potential

by Yagnesh Nagarajan, Grigori Y. Rychkov and Daniel J. Peet

Pharmaceuticals 2017, 10(2), 35; https://doi.org/10.3390/ph10020035 - 27 Mar 2017

Cited by 9 | Viewed by 5633

Abstract

Two transient receptor potential (TRP) channels—TRPA1 and TRPV3—are post-translationally hydroxylated, resulting in oxygen-dependent regulation of channel activity. The enzymes responsible are the HIF prolyl hydroxylases (PHDs) and the asparaginyl hydroxylase factor inhibiting HIF (FIH). The PHDs and FIH are well characterized for their [...] Read more.

Two transient receptor potential (TRP) channels—TRPA1 and TRPV3—are post-translationally hydroxylated, resulting in oxygen-dependent regulation of channel activity. The enzymes responsible are the HIF prolyl hydroxylases (PHDs) and the asparaginyl hydroxylase factor inhibiting HIF (FIH). The PHDs and FIH are well characterized for their hydroxylation of the hypoxic inducible transcription factors (HIFs), mediating their hypoxic regulation. Consequently, these hydroxylases are currently being targeted therapeutically to modulate HIF activity in anemia, inflammation, and ischemic disease. Modulating the HIFs by targeting these hydroxylases may result in both desirable and undesirable effects on TRP channel activity, depending on the physiological context. For the best outcomes, these hydroxylases could be therapeutically targeted in pathologies where activation of both the HIFs and the relevant TRP channels are predicted to independently achieve positive outcomes, such as wound healing and obesity. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels in Drug Discovery: Old Concepts & New Thoughts)

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Open AccessReview

Pathophysiological Significance of Dermatan Sulfate Proteoglycans Revealed by Human Genetic Disorders

by Shuji Mizumoto, Tomoki Kosho, Shuhei Yamada and Kazuyuki Sugahara

Pharmaceuticals 2017, 10(2), 34; https://doi.org/10.3390/ph10020034 - 27 Mar 2017

Cited by 25 | Viewed by 14537

Abstract

The indispensable roles of dermatan sulfate-proteoglycans (DS-PGs) have been demonstrated in various biological events including construction of the extracellular matrix and cell signaling through interactions with collagen and transforming growth factor-β, respectively. Defects in the core proteins of DS-PGs such as decorin and [...] Read more.

The indispensable roles of dermatan sulfate-proteoglycans (DS-PGs) have been demonstrated in various biological events including construction of the extracellular matrix and cell signaling through interactions with collagen and transforming growth factor-β, respectively. Defects in the core proteins of DS-PGs such as decorin and biglycan cause congenital stromal dystrophy of the cornea, spondyloepimetaphyseal dysplasia, and Meester-Loeys syndrome. Furthermore, mutations in human genes encoding the glycosyltransferases, epimerases, and sulfotransferases responsible for the biosynthesis of DS chains cause connective tissue disorders including Ehlers-Danlos syndrome and spondyloepimetaphyseal dysplasia with joint laxity characterized by skin hyperextensibility, joint hypermobility, and tissue fragility, and by severe skeletal disorders such as kyphoscoliosis, short trunk, dislocation, and joint laxity. Glycobiological approaches revealed that mutations in DS-biosynthetic enzymes cause reductions in enzymatic activities and in the amount of synthesized DS and also disrupt the formation of collagen bundles. This review focused on the growing number of glycobiological studies on recently reported genetic diseases caused by defects in the biosynthesis of DS and DS-PGs. Full article

(This article belongs to the Special Issue Glycosaminoglycans and Proteoglycans)

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Open AccessEditorial

An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2

by Joachim Jose, Marc Le-Borgne, Lorenzo A. Pinna and Mathias Montenarh

Pharmaceuticals 2017, 10(2), 33; https://doi.org/10.3390/ph10020033 - 23 Mar 2017

Cited by 3 | Viewed by 4150

Abstract

The 8th International Conference on Protein Kinase CK2 took place in Homburg, Germany, from 6 September to 9 September 2016.[...] Full article

(This article belongs to the Special Issue An Updated View on an Emerging Target: Selected Papers from the 8th International Conference on Protein Kinase CK2)

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Pharmaceuticals, Volume 10, Issue 2 (June 2017) – 25 articles

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