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939 KiB

Open AccessArticle

The Three Catecholics Benserazide, Catechol and Pyrogallol are GPR35 Agonists

by Huayun Deng and Ye Fang

Pharmaceuticals 2013, 6(4), 500-509; https://doi.org/10.3390/ph6040500 - 8 Apr 2013

Cited by 11 | Viewed by 7892

Abstract

Nearly 1% of all clinically used drugs are catecholics, a family of catechol-containing compounds. Using label-free dynamic mass redistribution and Tango β-arrestin translocation assays, we show that several catecholics, including benserazide, catechol, 3-methoxycatechol, pyrogallol, (+)-taxifolin and fenoldopam, display agonistic activity against GPR35. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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1028 KiB

Open AccessArticle

Dual-Color Bioluminescence Analysis for Quantitatively Monitoring G-Protein-Coupled Receptor and β-Arrestin Interactions

by A.K.M. Kafi, Mitsuru Hattori, Naomi Misawa and Takeaki Ozawa

Pharmaceuticals 2011, 4(3), 457-469; https://doi.org/10.3390/ph4030457 - 25 Feb 2011

Cited by 8 | Viewed by 9335

Abstract

G protein-coupled receptors (GPCRs) are crucial elements in mammalian signal transduction, and are considered to represent potent drug targets. We have previously developed a GPCR assay system in cultured cells based on complementation of split fragments of click beetle (Pyrearinus termitilluminans) [...] Read more.

G protein-coupled receptors (GPCRs) are crucial elements in mammalian signal transduction, and are considered to represent potent drug targets. We have previously developed a GPCR assay system in cultured cells based on complementation of split fragments of click beetle (Pyrearinus termitilluminans) luciferase. The interaction of GPCRs with its target, β-arrestin, resulted in strong emission of bioluminescence upon stimulation with its specific ligand. In this study, we improved precision of the GPCR assay system by using railroad worm (Phrixothrix hirtus) luciferase as an internal control. We generated stable cell lines harboring the railroad worm luciferase and quantitatively evaluate the extent of GPCR-β-arrestin interactions. We showed concentration-dependent bioluminescence responses for four GPCRs: β2-adrenoceptor, endothelin receptor type A, α2-adrenoceptor and human μ-opioid receptor. We also demonstrated that the variation of responses was reduced significantly by normalizing the data with bioluminescence from railroad worm luciferase. This assay system represents a simple and reliable approach for screening drug candidates in a high throughput manner. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Review

Jump to: Research, Other

249 KiB

Open AccessReview

Targeting Platelet Thrombin Receptor Signaling to Prevent Thrombosis

by Eric L. Wallace and Susan S. Smyth

Pharmaceuticals 2013, 6(8), 915-928; https://doi.org/10.3390/ph6080915 - 2 Aug 2013

Cited by 11 | Viewed by 12229

Abstract

Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more [...] Read more.

Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more comprehensive antithrombotic effects. We review the pathophysiology of atherothrombosis, platelet activation by thrombin, the role of platelet protease activated receptors (PAR), and the clinical data supporting their use. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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533 KiB

Open AccessReview

Pathophysiology of GPCR Homo- and Heterodimerization: Special Emphasis on Somatostatin Receptors

by Rishi K. Somvanshi and Ujendra Kumar

Pharmaceuticals 2012, 5(5), 417-446; https://doi.org/10.3390/ph5050417 - 27 Apr 2012

Cited by 21 | Viewed by 9110

Abstract

G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating [...] Read more.

G-protein coupled receptors (GPCRs) are cell surface proteins responsible for translating >80% of extracellular reception to intracellular signals. The extracellular information in the form of neurotransmitters, peptides, ions, odorants etc is converted to intracellular signals via a wide variety of effector molecules activating distinct downstream signaling pathways. All GPCRs share common structural features including an extracellular N-terminal, seven-transmembrane domains (TMs) linked by extracellular/intracellular loops and the C-terminal tail. Recent studies have shown that most GPCRs function as dimers (homo- and/or heterodimers) or even higher order of oligomers. Protein-protein interaction among GPCRs and other receptor proteins play a critical role in the modulation of receptor pharmacology and functions. Although ~50% of the current drugs available in the market target GPCRs, still many GPCRs remain unexplored as potential therapeutic targets, opening immense possibility to discover the role of GPCRs in pathophysiological conditions. This review explores the existing information and future possibilities of GPCRs as tools in clinical pharmacology and is specifically focused for the role of somatostatin receptors (SSTRs) in pathophysiology of diseases and as the potential candidate for drug discovery. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Open AccessReview

Functional and Structural Overview of G-Protein-Coupled Receptors Comprehensively Obtained from Genome Sequences

by Makiko Suwa, Minoru Sugihara and Yukiteru Ono

Pharmaceuticals 2011, 4(4), 652-664; https://doi.org/10.3390/ph4040652 - 13 Apr 2011

Cited by 18 | Viewed by 10669

Abstract

An understanding of the functional mechanisms of G-protein-coupled receptors (GPCRs) is very important for GPCR-related drug design. We have developed an integrated GPCR database (SEVENS http://sevens.cbrc.jp/) that includes 64,090 reliable GPCR genes comprehensively identified from 56 eukaryote genome sequences, and overviewed the sequences [...] Read more.

An understanding of the functional mechanisms of G-protein-coupled receptors (GPCRs) is very important for GPCR-related drug design. We have developed an integrated GPCR database (SEVENS http://sevens.cbrc.jp/) that includes 64,090 reliable GPCR genes comprehensively identified from 56 eukaryote genome sequences, and overviewed the sequences and structure spaces of the GPCRs. In vertebrates, the number of receptors for biological amines, peptides, etc. is conserved in most species, whereas the number of chemosensory receptors for odorant, pheromone, etc. significantly differs among species. The latter receptors tend to be single exon type or a few exon type and show a high ratio in the numbers of GPCRs, whereas some families, such as Class B and Class C receptors, have long lengths due to the presence of many exons. Statistical analyses of amino acid residues reveal that most of the conserved residues in Class A GPCRs are found in the cytoplasmic half regions of transmembrane (TM) helices, while residues characteristic to each subfamily found on the extracellular half regions. The 69 of Protein Data Bank (PDB) entries of complete or fragmentary structures could be mapped on the TM/loop regions of Class A GPCRs covering 14 subfamilies. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Open AccessReview

Molecular Approaches To Target GPCRs in Cancer Therapy

by Giulio Innamorati, Maria Teresa Valenti, Francesco Giovinazzo, Luca Dalle Carbonare, Marco Parenti and Claudio Bassi

Pharmaceuticals 2011, 4(4), 567-589; https://doi.org/10.3390/ph4040567 - 25 Mar 2011

Cited by 15 | Viewed by 10471

Abstract

Hundreds of G protein coupled receptor (GPCR) isotypes integrate and coordinate the function of individual cells mediating signaling between different organs in our bodies. As an aberration of the normal relationships that organize cells’ coexistence, cancer has to deceive cell-cell communication in order [...] Read more.

Hundreds of G protein coupled receptor (GPCR) isotypes integrate and coordinate the function of individual cells mediating signaling between different organs in our bodies. As an aberration of the normal relationships that organize cells’ coexistence, cancer has to deceive cell-cell communication in order to grow and spread. GPCRs play a critical role in this process. Despite the fact that GPCRs represent one of the most common drug targets, current medical practice includes only a few anticancer compounds directly acting on their signaling. Many approaches can be envisaged to target GPCRs involved in oncology. Beyond interfering with GPCRs signaling by using agonists or antagonists to prevent cell proliferation, favor apoptosis, induce maturation, prevent migration, etc., the high specificity of the interaction between the receptors and their ligands can be exploited to deliver toxins, antineoplastic drugs or isotopes to transformed cells. In this review we describe the strategies that are in use, or appear promising, to act directly on GPCRs in the fight against neoplastic transformation and tumor progression. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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707 KiB

Open AccessReview

Soft X-ray Laser Microscopy of Lipid Rafts towards GPCR-Based Drug Discovery Using Time-Resolved FRET Spectroscopy

by Motoyoshi Baba, Tohru Kozasa, Takao Hamakubo, Hiroto Kuroda, Kazuyuki Masuda, Shin Yoneya and Tatsuhiko Kodama

Pharmaceuticals 2011, 4(3), 524-550; https://doi.org/10.3390/ph4030524 - 14 Mar 2011

Viewed by 8797

Abstract

Many signaling molecules involved in G protein-mediated signal transduction, which are present in the lipid rafts and believed to be controlled spatially and temporally, influence the potency and efficacy of neurotransmitter receptors and transporters. This has focus interest on lipid rafts and the [...] Read more.

Many signaling molecules involved in G protein-mediated signal transduction, which are present in the lipid rafts and believed to be controlled spatially and temporally, influence the potency and efficacy of neurotransmitter receptors and transporters. This has focus interest on lipid rafts and the notion that these microdomains acts as a kind of signaling platform and thus have an important role in the expression of membrane receptor-mediated signal transduction, cancer, immune responses, neurotransmission, viral infections and various other phenomena due to specific and efficient signaling according to extracellular stimuli. However, the real structure of lipid rafts has not been observed so far due to its small size and a lack of sufficiently sophisticated observation systems. A soft X-ray microscope using a coherent soft X-ray laser in the water window region (2.3–4.4 nm) should prove to be a most powerful tool to observe the dynamic structure of lipid rafts of several tens of nanometers in size in living cells. We have developed for the X-ray microscope a new compact soft X-ray laser using strongly induced plasma high harmonic resonance. We have also developed a time-resolved highly sensitive fluorescence resonance energy transfer (FRET) system and confirmed protein-protein interactions coupled with ligands. The simultaneous use of these new tools for observation of localization of G-protein coupled receptors (GPCRs) in rafts has become an important and optimum tool system to analyze the dynamics of signal transduction through rafts as signaling platform. New technology to visualize rafts is expected to lead to the understanding of those dynamics and innovative development of drug discovery that targets GPCRs localized in lipid rafts. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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690 KiB

Open AccessReview

Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators

by Karla K.V. Haack and Nael A. McCarty

Pharmaceuticals 2011, 4(3), 509-523; https://doi.org/10.3390/ph4030509 - 14 Mar 2011

Cited by 20 | Viewed by 10129

Abstract

G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in [...] Read more.

G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in function as it is ubiquitously expressed among all cell types. Increasing evidence has shown that the classical two part model of GPCR signaling (one GPCR, one type of heterotrimeric G protein) is grossly oversimplified as many GPCRs can couple to more than one type of G protein, each subunit of the heterotrimeric G protein can activate different downstream effectors, and, surprisingly, other GPCRs can affect receptor behavior in G protein-independent ways. The concept of GPCR heterodimerization, or the physical association of two different types of GPCRs, presents an unexpected mechanism for GPCR regulation and function, and provides a novel target for pharmaceuticals. Here we present a synopsis of the functional consequences of GPCR heterodimerization in both in vitro and in vivo studies, focusing on the concept of GPCRs as allosteric modulators. Typically, an allosteric modulator is a ligand or molecule that alters a receptor’s innate functional properties, but here we propose that in the case of GPCR heterodimers, it is the physical coupling of two receptors that leads to changes in cognate receptor signaling. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Graphical abstract

289 KiB

Open AccessReview

Expanding the Concept of G Protein-Coupled Receptor (GPCR) Dimer Asymmetry towards GPCR-Interacting Proteins

by Maud Kamal, Pascal Maurice and Ralf Jockers

Pharmaceuticals 2011, 4(2), 273-284; https://doi.org/10.3390/ph4020273 - 25 Jan 2011

Cited by 11 | Viewed by 9343

Abstract

G protein-coupled receptors (GPCRs), major targets of drug discovery, are organized in dimeric and/or oligomeric clusters. The minimal oligomeric unit, the dimer, is composed of two protomers, which can behave differently within the dimer. Several examples of GPCR asymmetry within dimers at the [...] Read more.

G protein-coupled receptors (GPCRs), major targets of drug discovery, are organized in dimeric and/or oligomeric clusters. The minimal oligomeric unit, the dimer, is composed of two protomers, which can behave differently within the dimer. Several examples of GPCR asymmetry within dimers at the level of ligand binding, ligand-promoted conformational changes, conformational changes within transmembrane domains, G protein coupling, and most recently GPCR-interacting proteins (GIPs), have been reported in the literature. Asymmetric organization of GPCR dimers has important implications on GPCR function and drug design. Indeed, the extension of the “asymmetry concept” to GIPs adds a new level of specific therapeutic intervention. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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216 KiB

Open AccessReview

GPCRs Revisited: New Insights Lead to Novel Drugs

by Richard M. Eglen and Terry Reisine

Pharmaceuticals 2011, 4(2), 244-272; https://doi.org/10.3390/ph4020244 - 25 Jan 2011

Cited by 19 | Viewed by 8574

Abstract

GPCRs play a critical role in human physiology and are a prime target for drug discovery globally. Novel insights into the functions of GPCRs are providing unique approaches to modulate these proteins to generate unique drug candidates. Next generation ligands include those with [...] Read more.

GPCRs play a critical role in human physiology and are a prime target for drug discovery globally. Novel insights into the functions of GPCRs are providing unique approaches to modulate these proteins to generate unique drug candidates. Next generation ligands include those with novel pharmacologies such as allosteric regulators as well pepducins, that affect the interaction of GPCRs with G proteins, to either block selective receptor signaling pathways or mimic the actions of intracellular domains of receptors, thereby activating GPCRs to signal selectively to intracellular pathways. We will review these new concepts and then discuss how they may be exploited using modern discovery technologies to provide novel drug candidates for the future. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Open AccessReview

Original Fluorescent Ligand-Based Assays Open New Perspectives in G-Protein Coupled Receptor Drug Screening

by Martin Cottet, Orestis Faklaris, Jurriaan M. Zwier, Eric Trinquet, Jean-Philippe Pin and Thierry Durroux

Pharmaceuticals 2011, 4(1), 202-214; https://doi.org/10.3390/ph4010202 - 18 Jan 2011

Cited by 27 | Viewed by 12094

Abstract

The identification of new drugs exhibiting reduced adverse side-effects constitutes a great challenge for the next decade. Various steps are needed to screen for good ligand candidates and one of them is the evaluation of their binding properties. New strategies based on fluorescence [...] Read more.

The identification of new drugs exhibiting reduced adverse side-effects constitutes a great challenge for the next decade. Various steps are needed to screen for good ligand candidates and one of them is the evaluation of their binding properties. New strategies based on fluorescence measurement constitute excellent alternatives to the traditional radioactive assays. Less hazardous, faster and cheaper, these methods also exhibit very good sensitivity and can be used on various biological models such as heterologous expression systems or native tissues. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Open AccessReview

Sphingosine-1-Phosphate-Specific G Protein-Coupled Receptors as Novel Therapeutic Targets for Atherosclerosis

by Yasuo Okamoto, Fei Wang, Kazuaki Yoshioka, Noriko Takuwa and Yoh Takuwa

Pharmaceuticals 2011, 4(1), 117-137; https://doi.org/10.3390/ph4010117 - 4 Jan 2011

Cited by 10 | Viewed by 10170

Abstract

Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and [...] Read more.

Atherosclerosis is a chronic inflammatory process involving complex interactions of modified lipoproteins, monocyte-derived macrophages or foam cells, lymphocytes, endothelial cells (ECs), and vascular smooth muscle cells. Sphingosine-1-phosphate (S1P), a biologically active blood-borne lipid mediator, exerts pleiotropic effects such as cell proliferation, migration and cell-cell adhesion in a variety of cell types via five members of S1P-specific high-affinity G protein-coupled receptors (S1P₁-S1P₅). Among them, S1P₁, S1P₂ and S1P₃ are major receptor subtypes which are widely expressed in various tissues. Available evidence suggest that S1P and HDL-bound S1P exert atheroprotective effects including inhibition of leukocyte adhesion and stimulation of endothelial nitric oxide synthase (eNOS) in endothelial cells (ECs) through the activation of G_i signaling pathway via S1P₃ and probably S1P₁, although there is still controversy. FTY720, the phosphorylation product of which is a high-affinity agonist for all S1P receptors except S1P₂ and act as an immunosuppressant by downregulating S1P₁ on lymphocytes, inhibits atherosclerosis in LDL receptor-null mice and apoE-null mice through the inhibition of lymphocyte and macrophage functions and probably stimulation of EC functions, without influencing plasma lipid concentrations. In contrast to S1P₁ and S1P₃, S1P₂ facilitates atherosclerosis by activating G_12/13-Rho-Rho kinase (ROCK) in apoE-null mice. S1P₂ mediates transmigration of monocytes into the arterial intima, oxidized LDL accumulation and cytokine secretion in monocyte-derived macrophages, and eNOS inhibition and cytokine secretion in ECs through Rac inhibition, NF-kB activation and 3’-specific phosphoinositide phosphatase (PTEN) stimulation downstream of G_12/13-Rho-ROCK. Systemic long-term administration of a selective S1P₂-blocker remarkably inhibits atherosclerosis without overt toxicity. Thus, multiple S1P receptors positively and negatively regulate atherosclerosis through multitudes of mechanisms. Considering the essential and multi-faceted role of S1P₂ in atherogenesis and the impact of S1P₂ inactivation on atherosclerosis, S1P₂ is a particularly promising therapeutic target for atherosclerosis. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Open AccessReview

GPCR Conformations: Implications for Rational Drug Design

by Abby L. Parrill and Debra L. Bautista

Pharmaceuticals 2011, 4(1), 7-43; https://doi.org/10.3390/ph4010007 - 23 Dec 2010

Cited by 15 | Viewed by 10320

Abstract

G protein-coupled receptors (GPCRs) comprise a large class of transmembrane proteins that play critical roles in both normal physiology and pathophysiology. These critical roles offer targets for therapeutic intervention, as exemplified by the substantial fraction of current pharmaceutical agents that target members of [...] Read more.

G protein-coupled receptors (GPCRs) comprise a large class of transmembrane proteins that play critical roles in both normal physiology and pathophysiology. These critical roles offer targets for therapeutic intervention, as exemplified by the substantial fraction of current pharmaceutical agents that target members of this family. Tremendous contributions to our understanding of GPCR structure and dynamics have come from both indirect and direct structural characterization techniques. Key features of GPCR conformations derived from both types of characterization techniques are reviewed. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Open AccessReview

Jak2 Tyrosine Kinase: A Potential Therapeutic Target for AT₁ Receptor Mediated Cardiovascular Disease

by Annet Kirabo and Peter P. Sayeski

Pharmaceuticals 2010, 3(11), 3478-3493; https://doi.org/10.3390/ph3113478 - 9 Nov 2010

Cited by 7 | Viewed by 13269

Abstract

Patients with hypertension often manifest a dysregulated renin-angiotensin-aldosterone system (RAAS). Most of the available treatment approaches for hypertension are targeted towards the RAAS including direct renin inhibition, ACE inhibition, angiotensin II type 1 receptor (AT₁-R) blockade, and aldosterone receptor antagonism. The [...] Read more.

Patients with hypertension often manifest a dysregulated renin-angiotensin-aldosterone system (RAAS). Most of the available treatment approaches for hypertension are targeted towards the RAAS including direct renin inhibition, ACE inhibition, angiotensin II type 1 receptor (AT₁-R) blockade, and aldosterone receptor antagonism. The Jak2 signaling pathway is intricately coupled to the AT₁-R signaling processes involved in hypertension. Here, we review the involvement of Jak2 in the pathogenesis of hypertension, and its potential as a therapeutic target for treatment of AT₁-R mediated cardiovascular disease. Jak2 may provide a rational therapeutic approach for patients whose blood pressure is not controlled by standard therapies. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Open AccessReview

Role of the G Protein-Coupled Receptor, mGlu₁, in Melanoma Development

by Janet Wangari-Talbot, James Goydos and Suzie Chen

Pharmaceuticals 2010, 3(9), 2821-2837; https://doi.org/10.3390/ph3092821 - 26 Aug 2010

Cited by 4 | Viewed by 9998

Abstract

Melanoma remains one of the cancers for which a decline in morbidity has not been achieved with current scientific and medical advances. Mono-therapies targeting melanoma have been largely ineffective, increasing the need for identification of new drugable targets. Multiple tumor suppressors and oncogenes [...] Read more.

Melanoma remains one of the cancers for which a decline in morbidity has not been achieved with current scientific and medical advances. Mono-therapies targeting melanoma have been largely ineffective, increasing the need for identification of new drugable targets. Multiple tumor suppressors and oncogenes that impart genetic predisposition to melanoma have been identified and are being studied in an attempt to provide insight on the development of anti-melanoma therapies. Metabotropic Glutamate Receptor I (GRM1) has recently been implicated as a novel oncogene involved in melanomagenesis. GRM1 (mGlu₁, protein) belongs to the G protein coupled receptor (GPCR) super family and is normally functional in the central nervous system. Our group showed in a transgenic mouse model system that ectopic expression of Grm1 in melanocytes is sufficient to induce spontaneous melanoma development in vivo. GPCRs are some of the most important therapeutic drug targets discovered to date and they make up a significant proportion of existing therapies. This super family of transmembrane receptors has wide spread expression and interacts with a diverse array of ligands. Diverse physiological responses can be induced by stimulator(s) or suppressor(s) of GPCRs, which contributes to their attractiveness in existing and emerging therapies. GPCR targeting therapies are employed against a variety of human disorders including those of the central nervous system, cardiovascular, metabolic, urogenital and respiratory systems. In the current review, we will discuss how the identification of the oncogenic properties of GRM1 opens up new strategies for the design of potential novel therapies for the treatment of melanoma. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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Other

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236 KiB

Open AccessOpinion

Neuropeptide Receptors: Novel Targets for HIV/AIDS Therapeutics

by Donald R. Branch

Pharmaceuticals 2011, 4(3), 485-493; https://doi.org/10.3390/ph4030485 - 9 Mar 2011

Cited by 3 | Viewed by 8453

Abstract

The vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypepetide (VPAC) receptors are important for many physiologic functions, including glucose homeostasis, neuroprotection, memory, gut function, modulation of the immune system and circadian function. In addition, VPAC receptors have been shown to function in vitro to modulate [...] Read more.

The vasoactive intestinal peptide/pituitary adenylyl cyclase-activating polypepetide (VPAC) receptors are important for many physiologic functions, including glucose homeostasis, neuroprotection, memory, gut function, modulation of the immune system and circadian function. In addition, VPAC receptors have been shown to function in vitro to modulate the infection of HIV by a signal transduction pathway that appears to regulate viral integration. In this article, the affects of VPAC stimulation on HIV infection will be reviewed and approaches for the development of HIV/AIDS therapeutics that target these receptors will be described. Novel HIV/AIDS therapeutics are urgently required to stem the continued spread of this disease, particularly in underdeveloped countries. Drug design to inhibit signaling through VPAC1 and stimulate signaling through VPAC2 could lead to alternative therapies for the treatment and/or prevention of HIV/AIDS. Full article

(This article belongs to the Special Issue GPCR Based Drug Discovery)

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