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Tag: Compound

  • CN Bio raises $21 million USD in first close of Series B investment round

    CN Bio raises $21 million USD in first close of Series B investment round

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    Bayland Capital and founding shareholder, CN Innovations Holdings Ltd, to invest $10 M and $5.5 M, respectively. Investment will expand product development and scaling of the organization to meet increased demand for Organ-on-a-Chip (OOC) solutions.

    Image Credit: CN Bio

    CN Bio, a leading provider of single- and multi-organ microphysiological systems, today announced it has raised a $21 million investment in the first close of its Series B fundraising round. The funding has been secured from several new investors; including $10 million from Bayland Capital, and $5.5 million from founding shareholder, CN Innovations Holdings Ltd. The investment will be used to accelerate the Company’s expanding product portfolio and to scale the business to support commercial expansion across key global markets.

    The global OOC market’s CAGR is estimated at 30.94%. This growth has been accelerated, in part, by the need for biopharmaceutical companies to improve the efficiency and success rate of innovative drug R&D and recent legislative changes, such as the US FDA Modernization Act 2.0. In response, CN Bio is delivering an ambitious expansion strategy to meet the increasing demand for its PhysioMimix® OOC technology and research services, and to provide deeper, clinically-relevant insights into early-stage preclinical drug discovery in a wider range of application areas, whilst reducing reliance on animal models. Over the past year, this has included a series of high-profile appointments to expand the Company’s leadership team in the UK and US, new product launches, and strategic industry collaborations. Notably, in December 2023, it was confirmed that PhysioMimix® OOC and its associated NASH ‘in-a-box’ kit provided critical human-relevant compound efficacy data for Inipharm’s INI-822, supporting regulatory approval to initiate clinical testing for metabolic liver disease – a pivotal inflection point in CN Bio’s development, and the broader industry.

    With the latest fundraising, CN Bio is well-positioned to continue its global expansion to meet the evolving needs of customers worldwide in key markets including toxicology, drug pharmacology and metabolic diseases. With 80% of clinical failures attributed to efficacy and toxicity issues, often derived from the poor predictiveness of animal and 2D cell culture models, the industry demand for OOC solutions in these areas is growing. By expanding R&D in the space, CN Bio will enhance the depth and breadth of tools and applications available to optimize drug discovery and development workflows, enabling researchers to generate data with greater predictability, lower risks of late-stage failures, and accelerate time-to-market for a wide-range of novel therapeutics.

    We are seeing pivotal growth across our industry, whereby drug developers are increasingly recognising the potential of OOC technology to augment, supplement and optimize their workflows.”

    Dr Paul Brooks, CEO, CN Bio

    He added: “We have strategically positioned ourselves accordingly to respond to the market needs and are proud to have received recognition from our major shareholder, CN Innovations, and new institutional investors such as Bayland Capital, to drive this vision forward. The investment is a testament to our team’s hard work and dedication to best supporting our customers to bring drugs to patients more quickly, more cost-effectively, and through less animal experimentation.”

    Yuexing Su, Founding Partner, Bayland Capital, commented: “OOC technology is an exciting market with compelling opportunity for growth. CN Bio has taken key steps to build a team with extensive industry expertise and robust networks across the industry, with a longstanding track record of success. We look forward to the continued success for the Company as it further capitalizes on this unique growth opportunity and delivers on its future expansion plans to remain at the cutting-edge of the field. We will leverage our networks and shareholders’ base to further support and cement the leading position of CN Bio in OOC development.”

    Charles Chong, Managing Director, CN Innovations, added: “We are encouraged by CN Bio’s ongoing success and, in particular, the team’s achievements over the past years, during which conditions have been difficult in the broader economy. In this time, key milestones have been met, not just for the Company, but also the wider industry – including CN Bio providing critical human-relevant compound efficacy data to support the FDA’s approval for Inipharm’s Phase 1 clinical trial for metabolic liver disease. We are pleased to be supporting CN Bio again as it looks ahead and strengthens its future growth plans, of which, expanding its product portfolio in markets that hold huge impact for the industry, such as metabolic disease modelling and toxicology, will be key.”

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  • Expanding roles beyond cellular waste management

    Expanding roles beyond cellular waste management

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    The typical job of the proteasome, the garbage disposal of the cell, is to grind down proteins into smaller bits and recycle some of those bits and parts. That’s still the case, for the most part, but, Johns Hopkins Medicine researchers, studying nerve cells grown in the lab and mice, say that the proteasome’s role may go well beyond that.

    Its additional role, say the researchers, may shift from trash sorter to signal messenger in dorsal root ganglion neurons -; cells that convey sensory signals from nerve cells close to the skin to the central nervous system.

    Results of their experiments, published April 12 in Cell Reports, show that proteasomes may help those specialized neurons sense the surrounding environment, send signals to each other and potentially differentiate between sensing pain and itch, a finding that could help scientists better understand these sensory processes and new targets for treating pain and other sensory problems.

    Neurons live next to each other for a long time, and they need ways to communicate with each other about what they’re doing and who they are. Proteasomes in the membrane of neurons may help the cells fine tune this messaging process.”


    Seth S. Margolis, Ph.D., associate professor of biological chemistry, Johns Hopkins University School of Medicine

    “Proteasomes are more complicated than they appear,” says Margolis. He and his colleagues first found proteasomes in the plasma membranes of central nervous system neurons in mice in 2017, which they dubbed neuronal membrane proteasomes, and have continued studying how these special proteasomes promote messaging, or crosstalk, among neurons.

    At the time, Margolis’ focus was on the central nervous system, encompassing the brain and spinal cord. But later, he collaborated with neurobiologist Eric Villalón Landeros, Ph.D., postdoctoral fellow in Margolis’ laboratory at Johns Hopkins, whose work focuses on the peripheral nervous system, the network of neurons running through the rest of the body, closer to the skin, capturing sensory information from the environment.

    Margolis and Villalón Landeros wondered whether proteasomes could be found in peripheral neurons, and if so, what they might do.

    Using mouse antibodies that glom on to proteasomes, and other methods, the investigators found the proteasomes on the surface of neurons in the spinal cord, dorsal root ganglia, sciatic nerve and peripheral nerves innervating skin.

    The researchers were also able to find proteasomes in the same type of peripheral neurons grown in laboratory culture dishes.

    To understand the proteasome’s function in peripheral sensory neurons, the researchers gave mice biotin-epoxomicin, a cell membrane-impermeable proteasome inhibitor that blocks the function of neuronal membrane proteasomes. Then, they performed classic sensory tests.

    The researchers found that the mice that got injections of the proteasome-blocking drug biotin-epoxomicin on one side of the body were between 25% to 50% slower than the other side to respond to sensory tests.

    “This suggests that membrane proteasomes are important for sensation, and they must be facilitating this at the signaling level,” says Margolis.

    The researchers used single cell sequencing technology to determine that membrane proteasomes were expressed in a subpopulation of neurons involved in itch sensation and known to be sensitive to histamine, an immune system compound that launches an animal’s (including human’s) response to allergens.

    In laboratory culture dishes, the researchers stimulated both itch-related and non-itch related neurons and blocked their membrane proteasomes with biotin-epoxomicin. This resulted in changes to activity in all of the cells. “Blocking proteasomes seems to have an activity-modulatory effect across all the cells, despite being expressed in a subpopulation, suggesting that proteasomes facilitate a kind of cross talk between these cells,” says Margolis.

    Proteasome blockers, including one called Velcade, are currently used to treat certain types of cancer.

    Villalón Landeros and Margolis plan to continue working together to determine how neuronal membrane proteasomes function in sensory neurons and in sensing pain versus itch. “We want to see if we can manipulate neuronal membrane proteasomes to have a different outcome on pain and itch sensation,” says Villalón Landeros.

    Additional scientists who contributed to the research are Samuel Kho, Taylor Church, Anna Brennan, Fulya Türker, Michael Delannoy and Michael Caterina from Johns Hopkins.

    Funding for the research was provided by the National Institutes of Health (F32NS119202, R01 NS110754) and a Merkin Peripheral Neuropathy and Nerve Regeneration Center grant.

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  • Insilico Medicine’s AI-driven approach yields promising PTPN2/N1 inhibitor for cancer immunotherapy

    Insilico Medicine’s AI-driven approach yields promising PTPN2/N1 inhibitor for cancer immunotherapy

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    In recent years, cancer immunotherapy, exemplified by PD-1 and its ligand PD-L1 blockade, has made remarkable advances. But while immunotherapy drugs offer new treatment possibilities, only about 20% to 40% of patients respond to these treatments. The majority either don’t respond or develop drug resistance. Researchers are now looking for ways to enhance the scope of tumor immunotherapy in order to benefit a wider range of patients. 

    One such avenue is through the protein tyrosine phosphatase non-receptor type 2 (PTPN2) and its close superfamily member, PTPN1, identified in previous research as crucial modulators involved in the regulation of immune cells signaling pathways that promote tumorigenesis by attenuating tumor-directed immunity. While promising, the development of PTPN2/PTPN1 inhibitors has faced challenges as a result of unfavorable pharmacokinetics due to the highly cationic active site and the relatively shallow nature of the protein surface.

    In a significant milestone, researchers at Abbvie discovered the dual PTPN2/N1 inhibitor ABBV-CLS-484 through structure-based drug design and optimization of drug-like properties. Now, clinical stage artificial intelligence (AI)-driven drug discovery company Insilico Medicine (“Insilico”) has initiated a program with a fast-follow strategy to design a novel PTPN2/N1 inhibitor with drug-likeness properties and in vivo oral absorption, supported by the Company’s generative AI drug design engine Chemistry42. The research was published in the European Journal of Medicinal Chemistry on April 5.

    Scientists inputted the structure of the known PTPN2/N1 inhibitor as a reference compound to Chemistry42 as a starting point and generated a series of novel PTPN2/N1 inhibitors based on ligand-based drug design strategy. They further optimized and synthesized the most promising molecules and obtained candidates with desirable ADME properties. Insilico’s compound demonstrated enhanced oral absorption, systemic exposure, and equivalent biological activities compared to the reference compound in in vitro studies. Furthermore, Insilico’s compound demonstrated the same efficacious dose as the reference compound in murine model. 

    One of the most significant advances in the research was validating the fast follow ability of Chemistry42, the molecular generation and design engine of Pharma.AI, which allows users to rapidly improve existing molecules with more desirable properties. In this paper, we reported a novel PTPN2/PTPN1 inhibitor demonstrating nanomolar inhibitory potency, good in vivo oral bioavailability, and robust in vivo antitumor efficacy. Further investigation is currently ongoing.”


    Xiao Ding, PhD, vice president and head of medicinal chemistry of Insilico Medicine

    Insilico Medicine is a pioneer in using generative AI for drug discovery and development. The Company first described the concept of using generative AI for the design of novel molecules in a peer-reviewed journal in 2016. Then, Insilico developed and validated multiple approaches and features for its generative adversarial network (GAN)-based AI platform and integrated those algorithms into the commercially available Pharma.AI platform, which includes generative biology, chemistry, and medicine and has been used to produce a robust pipeline of promising therapeutic assets in multiple disease areas, including fibrosis, cancer, immunology and aging-related disease, a number of which have been licensed. Since 2021, Insilico has nominated 18 preclinical candidates in its comprehensive portfolio of over 30 assets and has advanced six pipelines to the clinical stage. In March 2024, the Company published a paper in Nature Biotechnology that discloses the raw experimental data and the preclinical and clinical evaluation of its lead drug – a potentially first-in-class TNIK inhibitor for the treatment of idiopathic pulmonary fibrosis discovered and designed using generative AI currently in Phase II trials with patients. 

    Source:

    Journal reference:

    Zheng, J., et al. (2024) Synthesis and structure-activity optimization of azepane-containing derivatives as PTPN2/PTPN1 inhibitors. European Journal of Medicinal Chemistry. doi.org/10.1016/j.ejmech.2024.116390.

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  • Metrion Biosciences enhances High Throughput Screening services with access to Enamine compound libraries

    Metrion Biosciences enhances High Throughput Screening services with access to Enamine compound libraries

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    Metrion Biosciences Limited (“Metrion”), the specialist ion channel and cardiac safety screening contract research organization (CRO) and drug discovery company, and Enamine Ltd (“Enamine”), the global leader in supplying small molecules and early drug discovery services, announced that Metrion has enhanced its High Throughput Screening (HTS) services with the addition of access to Enamine’s compound libraries.

    The Enamine compound library collection is the largest in the world and includes both CNS and ion channel-focused target libraries. The libraries can be split into discrete screening sets, enabling increased flexibility and efficiencies in screening and target identification. In addition, ‘analog-by-catalog’ from Enamine in-stock and ‘make-on-demand REAL libraries’ present a fast and economical solution for hit expansion and SAR (structure-activity relationships) studies.

    To ensure diversity and cost-efficiency, researchers can access specialist advice from Metrion’s team of ion channel and HTS experts to determine the most effective approach. The Company will also provide a Structured Data File of all libraries to compare against existing libraries, further increasing efficiency.

    Metrion’s HTS capabilities were launched in November 2022 as an addition to its extensive preclinical ion channel drug discovery and safety pharmacology services, to complement the Company’s automated and conventional electrophysiology services. Metrion’s HTS capabilities include 384 well screening via FLIPR Penta and Qube-384 systems. The services provide significant additional capacity and flexibility to support ion channel drug discovery projects for the Company’s global client base.

    The combination of our specialist ion channel expertise with substantial HTS and hit-finding experience gives customers access to a dedicated team of drug discovery scientists, ensuring the correct strategic choices are made in compounds selected for screening. This additional access to the highest quality screening libraries from Enamine increases diversity and enables Metrion to maximize R&D budgets even more effectively.

    Gary Clark, Director of Screening Technologies, Metrion Biosciences

    Enamine is focused on delivering novel chemical compounds to support drug discovery. We are delighted that Metrion is adding access to our libraries to its HTS services offering. Enamine is also able to support subsequent steps of the discovery process, including hit resupply, analoging from our in-stock and make-on-demand REAL libraries, and custom synthesis of advanced hits and leads.

    Vladimir Ivanov, Executive Vice President, Enamine

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  • New study to test novel psychedelic compound as potential treatment for alcohol use disorder

    New study to test novel psychedelic compound as potential treatment for alcohol use disorder

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    Modern mental health company Clerkenwell Health announced today that it is working with clinical-stage biotechnology company Beckley Psytech on a Phase IIa study investigating whether a novel psychedelic compound, combined with psychological support, could be an effective treatment for alcohol use disorder (AUD).

    NHS figures suggest over 7.5 million people in the UK live with AUD – commonly referred to as alcohol dependency.

    The open-label trial (NCT05674929), which is already underway at King’s College London, will evaluate the safety, tolerability and pharmacodynamic effects of a single dose of Beckley Psytech’s lead candidate, BPL-003, in combination with abstinence-oriented psychological support in participants with AUD. Participants will be followed for 12 weeks after initial dosing, with safety, pharmacokinetic and efficacy assessments conducted at multiple points throughout that period. The trial will now go ahead as well at Clerkenwell Health’s clinic near Harley Street, London and people interested in participating in this trial can register here. 

    BPL-003 is a novel, synthetic formulation of mebufotenin (5-MeO-DMT) which is a psychedelic of the tryptamine class naturally found in several plant species and the glands of at least one toad species. BPL-003 is administered intranasally and can elicit psychedelic experiences of similar intensity but shorter duration than psilocybin, which is found in ‘magic mushrooms’ and has shown early ​​​​​​​promise in substance abuse disorders.

    Treating AUDs is a pressing concern for the UK health system. Data from Public Health England shows there were 20,970 deaths related to alcohol in England in 2021, and from 2021 to 2022, there were 342,795 hospital admissions that were wholly due to alcohol, equating to 1 in 160 people.

    The results of this AUD trial may be used to provide support for further study of psychedelic-assisted treatment for alcohol dependency.

    Dr Henry Fisher, Chief Scientific Officer at Clerkenwell Health, said: “An estimated 600,000 people are dependent on alcohol in England. This, coupled with an alarming increase in alcohol-related deaths of 89% over the past 20 years, shows the status quo isn’t working. Conventional treatments for alcohol dependency aren’t producing meaningful improvements and new avenues must be explored. This trial will assess whether psychedelic-assisted treatment can be an effective therapy for alcohol use disorder, with the hope of rolling out the treatment widely. Health professionals and policymakers should seriously consider such treatments, which could be genuinely ground-breaking for the NHS and for the hundreds of thousands of people being treated for alcohol use disorder in the UK.”

    ​​​​​​​We’re committed to developing a transformative and effective treatment option for individuals struggling with alcohol use disorder. Based on our preclinical and Phase I data, we are optimistic about the potential therapeutic benefits of BPL-003 for substance use disorders and we are excited to evaluate the compound further in this clinical trial. I want to extend my thanks to the team at Clerkenwell Health and King’s, as well as to the patients who have joined, and will join, this study. Their participation, support and collaboration are absolutely critical to furthering research into this area of huge unmet need.”

    Dr Rob Conley, Chief Medical and Scientific Officer, Beckley Psytech

    A growing body of research suggests that psychedelic drugs could be a pioneering force in the treatment of complex mental health conditions including substance use disorders.

    The novel combination of staged psychological support and the administration of a psychedelic compound in the presence of a trained counsellor is a paradigm shift for the substance abuse disorder and mental health treatment sector which has seen no significant new treatment options developed for a number of decades.

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  • Promising new compound reduces alcohol dependence in animal studies

    Promising new compound reduces alcohol dependence in animal studies

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    Scripps Research scientists have found that LY2444296-;a compound that selectively blocks the kappa opioid receptor (KOP)-;may reduce drinking in cases of alcohol dependence in animal studies. The findings, which were published March 9, 2024, in Scientific Reports, could eventually inform new treatment options for people who experience alcohol use disorder (AUD).

    Compounds designed to selectively block the KOP are very promising because this receptor is involved in a lot of mental illnesses, such as anxiety and depression. The KOP system is also important in alcohol use disorder, so the idea is if it’s targeted and blocked, you can stop alcohol abuse.”


    Rémi Martin-Fardon, PhD, Associate Professor, Department of Molecular Medicine

    The KOP system controls brain circuits that affect a range of neurological processes, including addiction, emotion, pain and reward seeking. Both acute and chronic exposure to alcohol negatively affects this system, according to the study’s first author, Francisco Flores-Ramirez, PhD, a postdoctoral fellow at Scripps Research.

    For their study, Martin-Fardon and Flores-Ramirez sought to find out whether orally administering LY2444296 could decrease alcohol consumption in rats that formed alcohol dependency. The aim was to mitigate withdrawal symptoms, which would hypothetically lead to reduced alcohol intake. Once rats received LY2444296 at doses as low as 3 mg per kg following 8 hours of abstinence-;when acute withdrawal symptoms typically start-; withdrawal signs and alcohol consumption tapered down significantly. The researchers also determined that LY2444296 may be innocuous, as it had neither a positive nor negative effect on rats without alcohol dependency.

    Martin-Fardon and his team didn’t expect LY2444296 to reduce withdrawal signs after only 8 hours of alcohol abstinence because earlier studies showed that other compounds capable of binding to the KOP had no effect on alcohol withdrawal. The scientists don’t yet know why LY2444296 was effective in the present study, and they plan to investigate further.

    “People drink to get rid of the sensations of withdrawal,” Martin-Fardon says. He added that withdrawal is associated with physical pain, and that oftentimes, “the only thing that can fix the problem is to have a drink.” But if LY2444296 is taken before withdrawal symptoms begin, “you can decrease the symptoms, so you feel better and drink less.”

    Still, the question remains which specific parts of the brain are best targeted to mitigate withdrawal symptoms. Next on their agenda, Martin-Fardon and Flores-Ramirez hope to determine whether LY24444296 can block the effects of stress and other cues that can trigger alcohol relapse.

    “We’re also interested in what brain regions are changing as a function of alcohol dependence,” Flores-Ramirez says. “Maybe we could target them to see if the compound could reverse both drinking and relapse behavior.”

    Source:

    Scripps Research Institute

    Journal reference:

    Flores-Ramirez, F. J., et al. (2024). LY2444296, a κ-opioid receptor antagonist, selectively reduces alcohol drinking in male and female Wistar rats with a history of alcohol dependence. Scientific Reports. doi.org/10.1038/s41598-024-56500-9.

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  • AI-based analysis uncovers two plant extracts with potential as GLP-1 agonist weight loss pills

    AI-based analysis uncovers two plant extracts with potential as GLP-1 agonist weight loss pills

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    Two plant compounds with potential as GLP-1 agonist weight loss pills have been identified in an AI (artificial intelligence)-based study, the European Congress on Obesity (ECO 2024) (Venice 12-15 May), will hear.

    Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide and tirzepatide are highly effective at helping people lose weight. By mimicking the action of a hormone called GLP-1 and binding to and activating the GLP-1 receptor in cells, they reduce appetite and feelings of hunger, slow the release of food from the stomach and increase feelings of fullness after eating.

    There is, however, a need for alternatives, says Elena Murcia, of the Structural Bioinformatics and High-Performance Computing Research Group (BIO-HPC) & Eating Disorders Research Unit, Catholic University of Murcia (UCAM), Murcia, Spain.

    Although the effectiveness of current GLP-1 agonists has been demonstrated, there are some side-effects associated with their use – gastrointestinal issues such as nausea, vomiting, and mental health changes like anxiety and irritability. Recent data has also confirmed that when patients stop treatment they regain lost weight.


    In addition, most GLP-1 agonists are peptides – short chains of amino acids that can be degraded by stomach enzymes – and so they are currently more likely to be injected rather than taken orally.


    Drugs that aren’t peptides may have fewer side-effects and be easier to administer, meaning they could be given as pills rather than injections. Other recent research has highlighted two promising non-peptide compounds, TTOAD2 and orforglipron.


    These are synthetic and we were interested in finding natural alternatives.”


    Elena Murcia, of the Structural Bioinformatics and High-Performance Computing Research Group (BIO-HPC) & Eating Disorders Research Unit, Catholic University of Murcia

    Ms Murcia and colleagues used high-performance artificial intelligence (AI) techniques to identify non-peptide natural compounds that activate the GLP-1 receptor.

    “We focused on plant extracts and other natural compounds because they may have fewer side-effects,” says Ms Murcia. 

    Virtual screening was used to sift through more than 10,000 compounds to identify those that bound to the GLP-1 receptor.

    Next, further AI-based methods were used to look at how closely these bonds resembled those that occur between the GLP-1 hormone and its receptor. The 100 compounds that bound most similarly were then chosen for additional visual analysis, to determine whether they interacted with key residues – amino acids – on the receptor.

    Finally, a Venn diagram (a mathematical graph using overlapping circles) was compiled to identify the compounds with the highest potential as GLP1-R agonists.

    This resulted in a shortlist of 65 compounds, two of which, “Compound A” and “Compound B”, bound strongly to the key residues in a similar way to TTOAD2 and orforglipron. 

    Compound A and Compound B are derived from very common plants, extracts of which have been associated with beneficial effects on the human metabolism in the past. Further details of the plants and the compounds are being kept confidential until patents are granted. It is hoped both could be given in pill-form. The two compounds are now undergoing lab tests. 

    Ms Murcia says: “We are in the early stages of developing new GLP-1 agonists derived from natural sources. If our AI-based calculations confirmed in vitro and then in clinical trials, we will have other therapeutic options to manage obesity. 

    “Computer-based studies such as ours have key advantages, such as reductions in costs and time, rapid analysis of large data sets, flexibility in experimental design and the ability to identify and mitigate any ethical and safety risks before conducting experiments in the laboratory.

    “These simulations also allow us to take advantage of AI resources to analyze complex problems and so provide a valuable initial perspective in the search for new drugs.”

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  • New compound shows promise as a more effective treatment for schistosomiasis

    New compound shows promise as a more effective treatment for schistosomiasis

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    A newly developed compound is showing promise in animal studies as a more effective treatment for human schistosomiasis, an understudied tropical disease caused by parasitic worms. The spread of schistosomiasis, a disease responsible for nearly 12,000 deaths globally each year, has been documented in 78 nations.

    Although schistosomiasis transmission tends to occur in tropical and subtropical areas, climate change could shift it into new areas such as southern Europe. There is currently no vaccine available for the disease, which comes with severe clinical symptoms. The drug praziquantel is used for treatment. However, resistant mutations are reducing praziquantel’s efficacy, and the drug doesn’t kill the larval-stage parasites.

    Sevan N. Alwan, an assistant professor at The University of Texas Health Science Center at San Antonio, led the research team.

    The infection can become reactivated when the larva develop into adult parasites, which comes with more severe symptoms and higher transmission rates. The compound we developed overcomes the limitations of praziquantel by being effective against the larval stage and resistant strains.”


    Sevan N. Alwan, Assistant Professor, The University of Texas Health Science Center

    Alwan will present the research at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, which will be held March 23–26 in San Antonio.

    “In recent reports, the cure rates for praziquantel were 60% in Sub-Saharan Africa, where the disease is highly endemic,” said Alwan. “The drug limitations strongly warrant the need for new therapeutics with a distinctly different mechanism of action to reach a better cure rate.”

    The new compound was developed as part of the research team’s effort to design, synthesize and test reengineered derivatives of oxamniquine, which was previously used to treat patients with parasite but is no longer used due to drug resistance and limited effectiveness.

    The researchers developed and tested 350 compounds. Five of these killed human Schistosoma species as well as a praziquantel-resistant strain in animal models.

    One of these compounds, called CIDD-0149830, also killed larval parasites in experiments with cultured cells and a mouse model of the disease. In experimental groups of five female mice each, the number of larval worms was reduced by 71.7% with CIDD-0149830, while praziquantel reduced them by only 21.1%. The study also showed that CIDD-0149830 reduced the number of eggs more effectively.

    “In addition to being effective against the larval stage and resistant strains, CIDD-0149830 also overcomes the limitation of oxamniquine by being effective against two major species of the parasite in animal models and can effectively treat mixed infection by these two species,” Alwan said.

    Although the new results are promising, the researchers caution that they must still determine dosing for humans and perform safety and toxicity studies to make sure the treatment is safe for human use. They also plan to conduct experiments with male and female mice to assess whether sex influences the outcome of worm burden and morbidity.

    Source:

    American Society for Biochemistry and Molecular Biology

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  • New compound extracted from African catfish skin mucas exhibits powerful antibacterial properties

    New compound extracted from African catfish skin mucas exhibits powerful antibacterial properties

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    Scientists report they have extracted a compound with powerful antibacterial properties from the skin of farmed African catfish. Although additional testing is necessary to prove the compound is safe and effective for use as future antibiotic, the researchers say it could one day represent a potent new tool against antimicrobial-resistant bacteria such as extended-spectrum beta-lactamase (ESBL) producing E. coli.

    Hedmon Okella is a postdoctoral researcher at the University of California, Davis, and led the project.

    The global public health threat due to antimicrobial resistance necessitates the search for safe and effective new antibacterial compounds. In this case, fish-derived antimicrobial peptides present a promising source of potential leads.”


    Hedmon Okella, postdoctoral researcher, University of California, Davis

    Okella will present the new research at Discover BMB, the annual meeting of the American Society for Biochemistry and Molecular Biology, which is being held March 23–26 in San Antonio.

    For the study, the researchers extracted several peptides (short chains of amino acids) from African catfish skin mucus and used machine learning algorithms to screen them for potential antibacterial activity. They then chemically synthesized the most promising peptide, called NACAP-II, and tested its efficacy and safety on ESBL-E. coli and mammalian blood cells, respectively.

    These tests showed that NACAP-II caused the bacteria to break open, or lyse, without appearing to harm the mammalian blood cells. “Preliminary findings indicate that this promising peptide candidate potentially disrupts the bacterial cell envelope to cause lysis at a very low concentration,” Okella said.

    The place where the peptide was found -; in the mucus on the skin of farmed African catfish -; is not as unlikely as it may seem. As anyone who has tried to hold one can attest, fish are enveloped in a slippery layer of mucus. This mucus is known to protect the fish against infections by physically carrying germs off of the skin and by producing antimicrobial compounds such as the one Okella’s team isolated.

    Many existing medicines are based on compounds that were first found in nature, and scientists speculate that marine and aquatic organisms represent a particularly rich -; though largely untapped -; source of bioactive compounds.

    As a next step, the researchers plan to study the peptide’s effects in animal models and explore strategies to produce it inexpensively.

    “We are currently utilizing chemical synthesis to upscale the production of this peptide that we believe will one day be of use as drug candidate in the battle against antimicrobial resistance,” Okella said.

    Source:

    American Society for Biochemistry and Molecular Biology

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  • Nanoparticles turbocharge turmeric’s curcumin for enhanced health benefits

    Nanoparticles turbocharge turmeric’s curcumin for enhanced health benefits

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    A review article published in the journal Antioxidants provides a detailed overview of nanoparticle-based strategies to improve the bioavailability and bioactivity of curcumin.

    Study: Enhancing the Bioavailability and Bioactivity of Curcumin for Disease Prevention and Treatment. Image Credit: Microgen / ShutterstockStudy: Enhancing the Bioavailability and Bioactivity of Curcumin for Disease Prevention and Treatment. Image Credit: Microgen / Shutterstock

    Background

    Curcumin, turmeric’s main bioactive compound, is a polyphenol found in Curcuma longa roots. This compound has numerous health benefits, including anticancer, antioxidant, anti-inflammatory, anti-obesity, anti-diabetic, anti-microbial, wound-healing, and lipid-lowering properties.

    Curcumin has low bioavailability in human organs and is rapidly converted to a number of bioactive metabolites after intestinal absorption. Dried turmeric powder prepared from Curcuma longa roots contains about 2-5% of curcumin.

    Curcumin consumed through dietary sources is sufficient to impact the gut microbiota. However, due to rapid metabolism, the concentration of intact curcumin in the circulation becomes very low (sub-micromolar concentrations), which is insufficient to trigger cellular signaling and gene expression, as observed in in vitro studies with cultured cells.   

    Examples of curcumin nano-delivery systems.Examples of curcumin nano-delivery systems.

    Strategies to increase curcumin bioavailability

    Dietary curcumin is inefficiently absorbed across the intestinal epithelium and undergoes rapid metabolism and systemic elimination. In an aqueous solution with a neutral pH, the enol state of curcumin is formed, which reduces the stability of curcumin.

    Several nanoformulations have been developed to increase curcumin concentration in the circulation as well as in specific cells, tissues, and organelles. These nanoformulations have been designed to increase curcumin solubility, improve stability during gastrointestinal absorption, alter absorption routes, and inhibit detoxification enzymes using adjuvants.

    The latest generation of curcumin nanoformulations can increase free curcumin bioavailability in plasma by more than 100-fold and improve absorption, cellular uptake, permeability through the blood-brain barrier, and tissue distribution.

    Factors that improve curcumin bioavailability include composition, size, and route of administration of nanoparticles. Curcumin preparations with smaller-size nanoparticles have been found to increase bioavailability when administered orally. In contrast, larger-size nanoparticles have been found to increase bioavailability when administered intravenously.

    Curcumin nanoformulations can induce senescence in malignant and normal cells, thus effectively treating various cancer types and age-related diseases, including cardiometabolic diseases, neurodegenerative diseases, and liver, lung, and gastrointestinal diseases.

    Regarding mode of action, existing evidence indicates that curcumin acts as an antioxidant and anti-inflammatory compound to reduce the production of reactive oxygen species (ROS) and modulate cellular signaling and gene expression related to inflammatory pathways. These activities work synergistically to maintain homeostasis of cellular macromolecules (proteins, DNA, and lipids).

    These activities can be increased by incorporating curcumin in nanoparticle-based formulations, such as polymeric curcumin–bioperine–PLGA. The isomerization of curcumin to cis-trans curcumin is known to increase its ability to bind adenosine receptors. Incorporation of cis-trans curcumin into nanoformulations is considered to be a valuable strategy to increase its therapeutic efficacy against inflammatory diseases.        

    Regarding safety profile, recent clinical trials indicate that the majority of curcumin nanoformulations are well-tolerated and safe for use in humans.

    Anti-microbial activities

    Curcumin is known to exert an anti-microbial effect against both Gram-positive and Gram-negative bacteria, and this activity is beneficial for topical applications against skin infection and oral and intestinal applications. Moreover, curcumin can indirectly prevent infection by inhibiting bacterial growth in foods. 

    The anti-microbial activities of curcumin can be enhanced by incorporating it into nanoformulations. Administration of curcumin with other compounds, such as antibiotics, honey, or other polyphenols, can also increase its anti-microbial and biofilm inhibitory activities.

    Effects of curcumin nanoformulations in the gastrointestinal tract  

    Several nanotechnology-based systems, such as micelles, liposomes, exosomes, phospholipid complexes, nanoemulsions, nanostructured lipid carriers, and biopolymer nanoparticles, have been found to increase oral curcumin bioavailability.

    Nanoparticle curcumin called ‘Theracurmin’ has been found to suppress colitis in mice by modulating gut microbiota. Improvement in gut microbiota composition has also been achieved using nanobubble curcumin extract. Curcumin loaded with nanostructured lipid carriers has been found to reduce colonic inflammation in animals.

    The incorporation of curcumin in liposomes has been found to increase its anticancer activity by improving gastrointestinal absorption. Moreover, the administration of curcumin with other bioactive compounds, such as piperine and salsalate, has been found to increase curcumin bioavailability and bioactivity.

    Effects of curcumin nanoformulations in liver and adipose tissue  

    Curcumin nanoformulations with adjuvants, such as piperine and quercetin, have been found to increase its bioavailability and bioactivity significantly. Various nanotechnology-based delivery systems, such as micelles, liposomes, polymeric, metal, and solid lipid nanoparticles, have been found to increase curcumin bioavailability.

    The anti-inflammatory, antioxidant, and antifibrotic properties of curcumin make it a potential therapeutic compound for liver diseases. In liver diseases, curcumin nanoformulations have been found to increase its therapeutic efficacy by increasing curcumin solubility, bioavailability, and membrane permeability and improving its pharmacokinetics, pharmacodynamics, and biodistribution.   

    Effects of curcumin nanoformulations on the cardiovascular system   

    Curcumin encapsulated in carboxymethyl chitosan nanoparticles conjugated to a myocyte-specific homing peptide has been found to increase the cardiac bioavailability of curcumin. The formulation has also been found to improve cardiac function by reducing the expression of hypertrophy marker genes and apoptotic mediators.

    Several curcumin nanoformulations, such as hyaluronic acid-based nanocapsules, nanoparticles encapsulated in PLGA or nanoemulsion systems, have been found to increase the aqueous solubility of curcumin and subsequently prevent hypertension in animals. Similar cardio-protective effects have been observed using nanocurcumin polymer-based nanoparticles and curcumin and nisin-based polylactic acid nanoparticles. These formulations have been found to prevent myocardial damage and improve cardiac muscle functions.

    Effects of curcumin nanoformulations on the brain   

    Curcumin complexed with galactomannans has been found to have better blood-brain barrier permeability and higher efficacy in preventing neuroinflammation, anxiety, fatigue, and memory loss in both humans and animals.

    Curcumin-laden liposomes have been found to exert anti-amyloidogenic and anti-inflammatory effects in animal and cellular models of Alzheimer’s disease. Curcumin’s preventive activities against Alzheimer’s disease are associated with its ability to reduce amyloid-beta production and tau aggregation, which are major hallmarks of Alzheimer’s disease.   

    However, clinical trials involving patients with mild to moderate Alzheimer’s disease could not find any beneficial effect of curcumin in reducing disease biomarkers and improving cognitive functions.

    A recent clinical trial involving non-demented adults, on the other hand, has shown that oral curcumin treatment can improve memory and reduce amyloid and tau accumulation in the amygdala and hypothalamus.   

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