Genetic Engineering & Biotechnology News

JUN15 2018

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12 | JUNE 15, 2018 | Genetic Engineering & Biotechnology News | GENengnews.com Vivienne Raper, Ph.D. Over the last 30 years, cell signaling has come to play a major role in cell and molecular bi- ology research, as well as in drug discovery. The process by which cells communicate is— at its most fundamental—a description of life itself, and is implicated in areas of healthcare as diverse as treating heart disease, Alzheim- er's, and drug addiction. The process of cell signaling begins when a ligand, a signaling molecule such as a hor- mone or neurotransmitter, released by one cell interacts with a compatible receptor on another cell's surface. One of the largest and most varied group of membrane-protein receptors on eukaryotic cells are G-protein- coupled receptors (GPCRs). GPCRs mediate a huge range of functions within the human body, which makes them a popular target for drug development, and the focus of the 7th Focused Meeting on Cell Signalling, which took place last month at the East Midlands Conference Centre in Not- tingham, U.K. Among the topics covered at the meeting were microscopy techniques for visualizing individual molecules, and research targeting individual signaling pathways to re- duce drug side effects. Aiding Alzheimer's Patients Today, an estimated one third to one half of all marketed drugs bind to GPCRs. According to a 2016 review co-authored by Sophie Brad- ley, Ph.D., a research fellow at the Institute of Molecular Cell and Systems Biology, Univer- sity of Glasgow, their popularity as a drug tar- get is due to their versatility – they respond to a myriad of substances, including hormones, neurotransmitters, odorants and even light. Moreover, they selectively interact with small- molecule ligands in a way that can be repli- cated with synthetic molecule drugs (Figure 1). One potential GPCR target for drug discov- ery is the M1 muscarinic acetylcholine recep- tor (M1 mAChR). "We're interested in M1 mAChR as a therapeutic target for Alzheimer's disease," says Dr. Bradley, who co-authored a paper published in 2017 on targeting M1 mA- ChR in mice engineered to experience prion disease. She presented new published and un- published research at the 7th Focused Meeting. According to Dr. Bradley, the current frontline treatments for Alzheimer's are ace- tylcholinesterase inhibitors, which increase transmission of a signaling molecule, acetyl- choline, in the parasympathetic nervous sys- tem (PSNS). Acetylcholine signaling to key brain regions is reduced in Alzheimer's. Unfortunately, the non-specificity of ace- tylcholinesterase inhibitors means they have unpleasant side effects at higher doses. "Tar- geting M1 mAChR could provide a more se- lective approach," says Dr. Bradley. "By tar- geting M1 receptors in mice with degenera- tive disease, we reversed cognitive decline and increased the lifespan of the mice," she says. Dr. Bradley also explained how targeting the M1 mAChR receptor may have additional benefits in treating Alzheimer's. "Alzheimer's patients don't just suffer memory decline, but also experience a variety of other symptoms, such as listlessness and agitation," she says. Dr. Bradley and her team have discovered that targeting M1 mAChR could decrease hyper- anxiety and incessant movement, an indica- tor of agitation, in genetically modified mice. "This shows that, perhaps, by pharmacologi- cally targeting M1 mAChR in human beings, we can also reduce agitation." Choosing the Right Pathway Adverse side effects aren't just a problem for acetylcholinesterase inhibitors. Non-spe- cific interactions between pharmaceuticals and GPCRs explain—in part—why, accord- ing to a review co-authored by Dr. Bradley in 2016, only 15% of the around 390 non- odorant GPCRs in the human genome have been successfully targeted by drugs. To avoid this problem, researchers are be- ginning to study how drug candidates can trig- ger a cascade of undesirable processes within a cell by targeting multiple similar receptors or signaling pathways. "A large number of drug trials focused on the M1 receptor have failed," she says. "We wanted to work out which pathways generate these adverse responses." According to Dr. Bradley, her team is the first to target the M1 receptor by using chemo- genetic techniques in mice. Through selectively knocking out a phosphorylation-dependent signaling pathway, they discovered that cer- tain M1 receptor ligands triggered seizures. "Drugs should potentially be designed to pro- mote phosphorylation and hence reduce the likelihood of adverse responses," she says. Tackling Cardiovascular Disease Anthony Davenport, Ph.D., reader in car- diovascular pharmacology at the University of Cambridge, U.K., is also working to im- prove the selectivity of pharmaceuticals, fo- cused on cardiovascular drugs that target the apelin receptor (APJ), a GPCR activated by a peptide called apelin (Figure 2). "We're particularly into apelin because it has two beneficial effects when infused into humans: it causes the blood vessels to relax or dilate, and it increases the output of the heart," Dr. Davenport says. In cardiovascu- lar disease, the heart often loses its ability to pump, and the blood vessels narrow, forc- ing the heart to pump harder to force blood New Cell Signaling Pathways Mapped Drug Discovery Tissue oxygenation is a critical deter- minant of the overall wound healing process. Apart from fueling the high energy demands of tissue repair, tissue oxygen is expended to generate reactive oxygen species (ROS) at the injury site. In an open skin wound, infection is a common threat. It causes immune cells of the body to mount a "respiratory burst" where phagocytic oxidases utilize oxygen to generate ROS and its deriva- tives to disinfect the wound. Thus, the wound fluid is observed to be one of the compartments of the body with highest reported concentrations of hydrogen peroxide, an ROS. Reversible oxidation-reduction processes play a key role in multiple aspects of the wound healing process, says Chandan Sen, Ph.D., from the Ohio State University Wexner Medical Center, where he serves as executive director of the, Ohio State Comprehensive Wound Center. He is also editor-in-chief of Anti- oxidants & Redox Signaling, published by Mary Ann Liebert, Inc. "Almost all non-phagocytic cells at the wound site are equipped with enzy- matic systems to deliberately generate ROS for redox signaling. Redox signal- ing is directly implicated in epithelial migration that helps the epidermis cover the wound," says Dr. Sen. "Hydro- gen peroxide and nitric oxide work in tandem to draw vasculature to the site of tissue repair. The wound bed provides the extracellular matrix support for tis- sue repair." "Redox signaling is central to numer- ous aspects of collagen formation and maturation—processes that are respon- sible for healthy tensile strength of the repaired skin," continues Dr. Sen. "A defective extracellular matrix compromises skin biomechanics, thus causing wound recurrence, a major public health burden." "Of major concern are emergent findings reporting that the biofilm form of infection, often not detected by standard clinical tests, is able to arrest the ability of mammalian cells to enzymatically generate ROS," says Dr. Sen. "Such forms of infection, known to be associated with over two-thirds of all clinically presented chronic wounds, is likely to derail redox signaling cascades required for healthy repair of skin wounds. " n Role of Redox Signaling in Wound Healing Focus on Visualizing Signal Molecules and Reducing Drug Side Effects Figure 1. A hypothetical example of stimulus bias shows a GPCR that is able to couple to two distinct pathways, pathway A and pathway B. On the left, agonist A is able to activate pathway A preferentially compared with pathway B; whereas agonist B, on the right, has the opposite effect. The design of ligands that display selectivity for one pathway over another may offer a means of driving signaling down a therapeutically beneficial arm while minimizing signaling down pathways that lead to toxic/adverse outcomes. Figure supplied by Sophie Bradley, Ph.D. Text from Bradley and Tobin. Annu. Rev. Pharmacol. Toxicol. 2016.56.535-559. Doi 10.1146/annurev-pharmtox-011613-140012

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