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Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery.

Biomolecules & Therapeutics.2017;25(1):80-90. doi:10.4062/biomolther.2016.160

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P₁₋₅. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn’s disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.
Acute Kidney Injury ; Animals ; Clone Cells ; Cloning, Organism ; Colitis, Ulcerative ; Dermatomyositis ; Drug Discovery* ; Fingolimod Hydrochloride ; Graft Rejection ; In Vitro Techniques ; Liver Failure ; Mice ; Multiple Sclerosis ; Polymyositis ; Psoriasis ; Receptors, Lysosphingolipid* ; Second Messenger Systems ; Sphingosine* ; Stroke

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US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection.

Sungjin LEE ; Yoon Hee CHUNG ; Choongho LEE

Biomolecules & Therapeutics.2017;25(1):69-79. doi:10.4062/biomolther.2016.208

Viruses continue to evolve a new strategy to take advantage of every aspect of host cells in order to maximize their survival. Due to their central roles in transducing a variety of transmembrane signals, GPCRs seem to be a prime target for viruses to pirate for their own use. Incorporation of GPCR functionality into the genome of herpesviruses has been demonstrated to be essential for pathogenesis of many herpesviruses-induced diseases. Here, we introduce US28 of human cytomegalovirus (HCMV) as the best-studied example of virally-encoded GPCRs to manipulate host GPCR signaling. In this review, we wish to summarize a number of US28-related topics including its regulation of host signaling pathways, its constitutive internalization, its structural and functional analysis, its roles in HCMV biology and pathogenesis, its proliferative activities and role in oncogenesis, and pharmacological modulation of its biological activities. This review will aid in our understanding of how pathogenic viruses usurp the host GPCR signaling for successful viral infection. This kind of knowledge will enable us to build a better strategy to control viral infection by normalizing the virally-dysregulated host GPCR signaling.
Biology ; Carcinogenesis ; Cytomegalovirus Infections* ; Cytomegalovirus* ; Genome ; Herpesviridae ; Humans*

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Evolutionary and Comparative Genomics to Drive Rational Drug Design, with Particular Focus on Neuropeptide Seven-Transmembrane Receptors.

Michael FURLONG ; Jae Young SEONG

Biomolecules & Therapeutics.2017;25(1):57-68. doi:10.4062/biomolther.2016.199

Seven transmembrane receptors (7TMRs), also known as G protein-coupled receptors, are popular targets of drug development, particularly 7TMR systems that are activated by peptide ligands. Although many pharmaceutical drugs have been discovered via conventional bulk analysis techniques the increasing availability of structural and evolutionary data are facilitating change to rational, targeted drug design. This article discusses the appeal of neuropeptide-7TMR systems as drug targets and provides an overview of concepts in the evolution of vertebrate genomes and gene families. Subsequently, methods that use evolutionary concepts and comparative analysis techniques to aid in gene discovery, gene function identification, and novel drug design are provided along with case study examples.
Drug Design* ; Gene Duplication ; Genetic Association Studies ; Genome ; Genomics* ; Humans ; Ligands ; Neuropeptides* ; Vertebrates

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β-Adrenergic Receptor and Insulin Resistance in the Heart.

Supachoke MANGMOOL ; Tananat DENKAEW ; Warisara PARICHATIKANOND ; Hitoshi KUROSE

Biomolecules & Therapeutics.2017;25(1):44-56. doi:10.4062/biomolther.2016.128

Insulin resistance is characterized by the reduced ability of insulin to stimulate tissue uptake and disposal of glucose including cardiac muscle. These conditions accelerate the progression of heart failure and increase cardiovascular morbidity and mortality in patients with cardiovascular diseases. It is noteworthy that some conditions of insulin resistance are characterized by up-regulation of the sympathetic nervous system, resulting in enhanced stimulation of β-adrenergic receptor (βAR). Over-stimulation of βARs leads to the development of heart failure and is associated with the pathogenesis of insulin resistance in the heart. However, pathological consequences of the cross-talk between the βAR and the insulin sensitivity and the mechanism by which βAR over-stimulation promotes insulin resistance remain unclear. This review article examines the hypothesis that βARs over-stimulation leads to induction of insulin resistance in the heart.
Cardiovascular Diseases ; Cyclic AMP-Dependent Protein Kinases ; Glucose ; Heart Diseases ; Heart Failure ; Heart* ; Humans ; Insulin Resistance* ; Insulin* ; Mortality ; Myocardium ; Sympathetic Nervous System ; Up-Regulation

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Multifactorial Regulation of G Protein-Coupled Receptor Endocytosis.

Xiaohan ZHANG ; Kyeong Man KIM

Biomolecules & Therapeutics.2017;25(1):26-43. doi:10.4062/biomolther.2016.186

Endocytosis is a process by which cells absorb extracellular materials via the inward budding of vesicles formed from the plasma membrane. Receptor-mediated endocytosis is a highly selective process where receptors with specific binding sites for extracellular molecules internalize via vesicles. G protein-coupled receptors (GPCRs) are the largest single family of plasma-membrane receptors with more than 1000 family members. But the molecular mechanisms involved in the regulation of GPCRs are believed to be highly conserved. For example, receptor phosphorylation in collaboration with β-arrestins plays major roles in desensitization and endocytosis of most GPCRs. Nevertheless, a number of subsequent studies showed that GPCR regulation, such as that by endocytosis, occurs through various pathways with a multitude of cellular components and processes. This review focused on i) functional interactions between homologous and heterologous pathways, ii) methodologies applied for determining receptor endocytosis, iii) experimental tools to determine specific endocytic routes, iv) roles of small guanosine triphosphate-binding proteins in GPCR endocytosis, and v) role of post-translational modification of the receptors in endocytosis.
Binding Sites ; Cell Membrane ; Cooperative Behavior ; Endocytosis* ; Glycosylation ; Guanosine ; Humans ; Lipoylation ; Phosphorylation ; Protein Processing, Post-Translational

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Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology.

Zuzana BOLOGNA ; Jian Peng TEOH ; Ahmed S BAYOUMI ; Yaoliang TANG ; Il man KIM

Biomolecules & Therapeutics.2017;25(1):12-25. doi:10.4062/biomolther.2016.165

G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of β-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or β-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.
Bias (Epidemiology)* ; Felodipine ; GTP-Binding Proteins ; Humans ; Ligands ; Pathology* ; Physiology* ; Transducers

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Recent Progress in Understanding the Conformational Mechanism of Heterotrimeric G Protein Activation.

Nguyen Minh DUC ; Hee Ryung KIM ; Ka Young CHUNG

Biomolecules & Therapeutics.2017;25(1):4-11. doi:10.4062/biomolther.2016.169

Heterotrimeric G proteins are key intracellular coordinators that receive signals from cells through activation of cognate G protein-coupled receptors (GPCRs). The details of their atomic interactions and structural mechanisms have been described by many biochemical and biophysical studies. Specifically, a framework for understanding conformational changes in the receptor upon ligand binding and associated G protein activation was provided by description of the crystal structure of the β2-adrenoceptor-Gs complex in 2011. This review focused on recent findings in the conformational dynamics of G proteins and GPCRs during activation processes.
GTP-Binding Proteins* ; Heterotrimeric GTP-Binding Proteins

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Conceptual Progress for the Improvements in the Selectivity and Efficacy of G Protein-Coupled Receptor Therapeutics: An Overview.

Kyeong Man KIM

Biomolecules & Therapeutics.2017;25(1):1-3. doi:10.4062/biomolther.2016.262

No abstract available.
Computational Biology ; Insulin Resistance

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Erratum to "Microfluidic System Based High Throughput Drug Screening System for Curcumin/TRAIL Combinational Chemotherapy in Human Prostate Cancer PC3 Cells" Biomol. Ther. 22 (2014) 355-362.

Dami AN ; Kwangmi KIM ; Jeongyun KIM

Biomolecules & Therapeutics.2014;22(5):475-475. doi:10.4062/biomolther.2014.475

The authors request to correct the project number NRF-2013R1A1A1010734 from NRF-116436 on the 4th line of Acknowledgments section.

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Erratum to "L-Tetrahydropalmatine Ameliorates Development of Anxiety and Depression-Related Symptoms Induced by Single Prolonged Stress in Rats" Biomol. Ther. 22 (2014) 213-222.

Bombi LEE ; Bongjun SUR ; Mijung YEOM ; Insop SHIM ; Hyejung LEE ; Dae Hyun HAHM

Biomolecules & Therapeutics.2014;22(5):474-474. doi:10.4062/biomolther.2014.474

In the article, incorrect images were placed in Fig. 8.

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