Bristol Laboratories Ltd.

Scientists have discovered why some coronaviruses are more likely to cause severe disease, which has remained a mystery, until now. Researchers of the University of Bristol-led study, published in Science Advances today, say their findings could lead to the development of a pan-coronavirus treatment to defeat all coronaviruses - from the 2002 SARS-CoV outbreak to Omicron, the current variant of SARS-CoV-2, as well as dangerous variants that may emerge in future. In this new study, an international team, led by Bristols Professor Christiane Schaffitzel, scrutinised the spike glycoproteins decorating all coronaviruses. They reveal that a tailor-made pocket feature in the SARS-CoV-2 spike protein, first discovered in 2020, is present in all deadly coronaviruses, including MERS and Omicron. In striking contrast, the pocket feature is not present in coronaviruses which cause mild infection with cold-like symptoms. The team say their findings suggest that the pocket, which binds a small molecule, linoleic acid - an essential fatty acid indispensable for many cellular functions including inflammation and maintaining cell membranes in the lungs so that we can breathe properly - could now be exploited to treat all deadly coronaviruses, at the same time rendering them vulnerable to a linoleic acid-based treatment targeting this pocket. COVID-19, caused by SARS-CoV-2, is the third deadliest coronavirus outbreak following SARS-CoV in 2002 and MERS-CoV in 2012. The much more infectious SARS-CoV-2 continues to infect people and damage communities and economies worldwide, with new variants of concern emerging successively, and Omicron evading vaccination and immune response. Professor Schaffitzel from Bristols School of Biochemistry, explained: In our earlier work we identified the presence of a small molecule, linoleic acid, buried in a tailor-made pocket within the SARS-Cov-2 glycoprotein, known as the Spike protein, which binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage. "We showed that binding linoleic acid in the pocket could stop virus infectivity, suggesting an anti-viral treatment. This was in the original Wuhan strain that started the pandemic. Since then, a whole range of dangerous SARS-CoV-2 variants have emerged, including Omicron, the currently dominating variant of concern. We scrutinised every new variant of concern and asked whether the pocket function is still present." Omicron has undergone many mutations, enabling it to escape immune protection offered by vaccination or antibody treatments that lag behind this rapidly evolving virus. Intriguingly, while everything else may have changed, the researchers found that the pocket remained virtually unaltered, also in Omicron. Christine Toelzer, Research Associate in the School of Biochemistry and lead author of the study, added: "When we realised that the pocket we had discovered remained unchanged, we looked back and asked whether SARS-CoV and MERS-CoV, two other deadly coronaviruses causing previous outbreaks years ago, also contained this linoleic acid binding pocket feature." The team applied high-resolution electron cryo-microscopy, cutting-edge computational approaches and cloud computing. Their results showed that SARS-CoV and MERS-CoV also had the pocket, and could bind the ligand, linoleic acid, by a virtually identical mechanism. Professor Schaffitzel concluded: "In our current study, we provide evidence that the pocket remained the same in all deadly coronaviruses, from the first SARS-CoV outbreak 20 years ago to Omicron today. We have shown previously that linoleic acid binding to this pocket induces a locked spike, abrogating viral infectivity. We also show now that linoleic acid supplementation suppresses virus replication inside cells. We anticipate that future variants will also contain the pocket, which we can exploit to defeat the virus." Halo Therapeutics, a recent University of Bristol spin-out Professor Schaffitzel co-founded, is using these findings to develop pocket-binding pan-coronavirus antivirals. The team included experts from the Bristol UNCOVER Group, Max Planck Bristol Centre for Minimal Biology, Bristol University spin-out Halo Therapeutics Ltd, and collaborators in Sweden and France. The studies have been supported by funds from Max Planck Gesellschaft, Wellcome Trust and European Research Council, with additional support from Oracle for Research for high-performance cloud computing resources. Christine Toelzer, Kapil Gupta, Sathish KN Yadav, Lorna Hodgson, Maia Kavanagh Williamson, Dora Buzas, Ufuk Borucu, Kyle Powers, Richard Stenner, Kate Vasileiou, Frederic Garzoni, Daniel Fitzgerald, Christine Payr, Gunjan Gautam, Grard Lambeau, Andrew D Davidson, Paul Verkade, Martin Frank, Imre Berger, Christiane Schaffitzel. The free fatty acid-binding pocket is a conserved hallmark in pathogenic -coronavirus spike proteins from SARS-CoV to Omicron. Science Advances, 2022. doi: 10.1126/sciadv.adc9179

Scientists have harnessed the potential of bacteria to help build advanced synthetic cells which mimic real life functionality. Scientists have harnessed the potential of bacteria to help build advanced synthetic cells which mimic real life functionality. The research, led by the University of Bristol and published today in Nature, makes important progress in deploying synthetic cells, known as protocells, to more accurately represent the complex compositions, structure, and function of living cells. Establishing true-to-life functionality in protocells is a global grand challenge spanning multiple fields, ranging from bottom-up synthetic biology and bioengineering to origin of life research. Previous attempts to model protocells using microcapsules have fallen short, so the team of researchers turned to bacteria to build complex synthetic cells using a living material assembly process. Professor Stephen Mann from the University of Bristol's School of Chemistry, and the Max Planck Bristol Centre for Minimal Biologytogether with colleagues Drs Can Xu, Nicolas Martin (currently at the University of Bordeaux) and Mei Li in the Bristol Centre for Protolife Research have demonstrated an approach to the construction of highly complex protocells using viscous micro-droplets filled with living bacteria as a microscopic building site. In the first step, the team exposed the empty droplets to two types of bacteria. One population spontaneously was captured within the droplets while the other was trapped at the droplet surface. Then, both types of bacteria were destroyed so that the released cellular components remained trapped inside or on the surface of the droplets to produce membrane-coated bacteriogenic protocells containing thousands of biological molecules, parts and machinery. The researchers discovered that the protocells were able to produce energy-rich molecules (ATP) via glycolysis and synthesize RNA and proteins by in vitro gene expression, indicating that the inherited bacterial components remained active in the synthetic cells. Further testing the capacity of this technique, the team employed a series of chemical steps to remodel the bacteriogenic protocells structurally and morphologically. The released bacterial DNA was condensed into a single nucleus-like structure, and the droplet interior infiltrated with a cytoskeletal-like network of protein filaments and membrane-bounded water vacuoles. As a step towards the construction of a synthetic/living cell entity, the researchers implanted living bacteria into the protocells to generate self-sustainable ATP production and long-term energization for glycolysis, gene expression and cytoskeletal assembly. Curiously, the protoliving constructs adopted an amoeba-like external morphology due to on-site bacterial metabolism and growth to produce a cellular bionic system with integrated life-like properties. Corresponding author Professor Stephen Mann said: "Achieving high organisational and functional complexity in synthetic cells is difficult especially under close-to-equilibrium conditions. Hopefully, our current bacteriogenic approach will help to increase the complexity of current protocell models, facilitate the integration of myriad biological components and enable the development of energised cytomimetic systems." First author Dr Can Xu, Research Associate at the University of Bristol, added: "Our living-material assembly approach provides an opportunity for the bottom-up construction of symbiotic living/synthetic cell constructs. For example, using engineered bacteria it should be possible to fabricate complex modules for development in diagnostic and therapeutic areas of synthetic biology as well as in biomanufacturing and biotechnology in general."

Alimera Sciences, Inc. (Nasdaq: ALIM) (“Alimera”), a global pharmaceutical company whose mission is to be invaluable to patients, physicians and partners concerned with retinal health and maintaining better vision longer, announces that Alimera Sciences Europe Limited, its Ireland-based European subsidiary, will launch ILUVIEN® for non-infectious posterior uveitis in Spain, through its distribution partner, Brill Pharma (Brill). Brill has received a positive resolution for the pricing and reimbursement approval for ILUVIEN for prevention of relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye from the Spanish Ministry of Health. “We are pleased to begin 2022 with this launch in Spain, our third major market to add the posterior uveitis indication,” said Rick Eiswirth, President and Chief Executive Officer of Alimera. “ILUVIEN is the first and only treatment to deliver drug for up to thirty-six months, reducing the recurrence of symptoms of disease, and enabling patients to see better, longer with fewer injections.” ILUVIEN is a sustained release intravitreal implant indicated in Europe for the treatment of vision impairment associated with chronic diabetic macular edema (DME) considered insufficiently responsive to available therapies and for prevention of relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye (NIPU). About ILUVIEN The Company’s primary product is ILUVIEN (fluocinolone acetonide intravitreal implant) 0.19 mg sustained release intravitreal implant, injected into the back of the eye. With its CONTINUOUS MICRODOSING™ technology, ILUVIEN is designed to release sub-microgram levels of fluocinolone acetonide, a corticosteroid, for 36 months, to reduce the recurrence of disease, enabling patients to maintain vision longer with fewer injections. ILUVIEN is approved in the U.S., Canada, Kuwait, Lebanon and the U.A.E to treat diabetic macular edema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. In 17 European countries, ILUVIEN is indicated for the treatment of vision impairment associated with chronic DME considered insufficiently responsive to available therapies. In March 2019, ILUVIEN received approval in the 17 countries under the Mutual Recognition Procedure for prevention of relapse in recurrent non-infectious uveitis affecting the posterior segment of the eye. The 17 European countries include the U.K., Germany, France, Italy, Spain, Portugal, Ireland, Austria, Belgium, Denmark, Norway, Finland, Sweden, Poland, Czechia, the Netherlands, and Luxembourg. The non-infectious posterior uveitis indication for ILUVIEN was launched in Germany and the U.K. in 3Q 2019. ILUVIEN is not approved for treatment of uveitis in the United States. About Non-Infectious Posterior Uveitis (NIPU) Posterior segment non-infectious uveitis is a chronic, inflammatory disease affecting the posterior segment of the eye, often involving the retina, and is a leading cause of blindness in developed and developing countries. It affects people of all ages, producing swelling and destroying eye tissues, which can lead to severe vision loss and blindness. Patients with NIPU are typically treated with systemic steroids, which are effective, but over time frequently lead to serious side effects, ranging from acne, weight gain, sleep and mood disorders to hypertension and osteoporosis that can limit effective dosing. Patients then often progress to steroid-sparing therapy with systemic immune suppressants or biologics, which also can have severe side effects, including an increased risk of cancer and infection. As a result, there remains a significant need for new therapies with improved efficacy, tolerability, and safety profiles to manage this disease. About Alimera Sciences, Inc. Alimera Sciences a global pharmaceutical company whose mission is to be invaluable to patients, physicians and partners concerned with retinal health and maintaining better vision longer. About Brill Pharma S.L Brill Pharma, the Spanish subsidiary of Bristol Laboratories U.K., is based in Barcelona, Spain and was established in September 2012. It markets innovative products in ophthalmology, is ranked second in this specific segment of the Spanish pharma market and was recognized as the fastest growing Spanish pharma company in its segment. The company employs more than 80 medical representatives covering Spain.