Drug Discovery Unit, University of Dundee’s Post

Researchers at Weill Cornell Medicine and Van Andel Institute have provided crucial structural insights into the interaction between a new antimalarial drug candidate, TDI-8304, and the malaria parasite Plasmodium falciparum. TDI-8304, targeting the proteasome of P. falciparum, has shown potent efficacy in preclinical studies, effectively killing parasites at multiple life cycle stages. Using cryo-electron microscopy (cryo-EM), the team demonstrated how TDI-8304 binds to its target and how mutations in P. falciparum confer resistance by altering these interactions. Notably, these mutations also increase sensitivity to other proteasome-targeting compounds, offering a potential strategy to delay resistance. The study highlights the potential for developing new antimalarial therapies that exploit these structural insights to overcome drug resistance. Read more Hsu HC, Li D, Zhan W, et al. Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors. Nat Commun. 2023;14(1):8302. https://lnkd.in/gM2zd47x

🤔  How can structural insights gained through cryo-EM help us develop drugs that are species-specific? 🦟  Species selectivity is a major concern for the development of proteasome inhibitors to treat malaria, with many clinical candidates targeting both the parasitic Plasmodium falciparum (Pf) proteasome and the human #proteasome. 🔬 In “Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria”, Lawong et al. use cryo-EM to solve the structure of a new #malaria drug in complex with the Pf proteasome. This structure reveals that the compound binds in a previously unexplored pocket which has significant differences between the Pf and human proteasomes. 💊 Identification of this novel binding site paves the way for the development of malaria therapeutics that target the proteasome with greater selectivity and fewer side effects. 📖  Read the study here: https://lnkd.in/gCGDAaAF 👩🔬 To learn more about how #cryoEM can be used to characterize proteasome inhibitors or identify novel binding sites, schedule a meeting with us today: https://lnkd.in/gTnWGWhp

🔬 Advancing Malaria Research with Cost-Effective Liver Stage Screening The fight against malaria faces challenges, including rising resistance to artemisinin-based drugs. Innovative approaches are crucial, and a newly adapted luciferase detection protocol offers hope. This protocol: ✅ Screens liver-stage Plasmodium berghei parasites at 20x lower cost than commercial kits. ✅ Identifies potent compounds like MMV674132 (30.2 nM potency). ✅ Enables efficient, high-throughput anti-malarial drug development. By addressing asymptomatic liver stages, this method enhances our ability to develop comprehensive treatments. #MalariaResearch #DrugDevelopment #GlobalHealth

A malaria drug could help treat polycystic ovary syndrome Artemisinin treatment alleviated the symptoms of PCOS in animal models and in 19 patients recruited to a pilot clinical trial. Artemisinin is an anti-malarial drug, but prior studies suggested systemic effects, including protection against metabolic disorders. Liu et al. evaluated the effects of artemisinin on PCOS, beginning with rat and mouse models. Animal studies showed that artemisinin alleviated signs of PCOS, not through metabolic effects but by reducing androgen excess — a driver of many PCOS symptoms. The mechanism involved increased degradation of the enzyme CYP11A1 by the protease LONP1 (whose overexpression mimicked the androgen-lowering effects of the drug). The researchers then conducted a pilot clinical study involving 19 people with PCOS. Patients were treated with artemisinin for 12 weeks, then were followed up for 12 weeks. Treatment significantly reduced levels of testosterone and anti-mullerian hormone (a marker of PCOS) and led to normalization of menstrual cycles in almost two thirds of patients, with no safety concerns. This study reveals artemisinin as a promising candidate therapy for PCOS, and highlights additional avenues for therapeutic development, such as targeting the LONP1–CYP11A1 interaction. https://lnkd.in/eBUdckfC #ClinicalResearch #MedicalResearch #ClinicalTrials #ResearchInnovation #HealthcareResearch #PharmaResearch #BioTech #MedTech #DrugDevelopment #PatientCare #EvidenceBasedMedicine #ClinicalStudy #ResearchAndDevelopment #HealthInnovation #TranslationalResearch

🌟 Exciting News in the Fight Against #Ebola! 🌟 Dear Connections, We are excited to announce the launch of AEPDB (Anti-Ebola Peptide Database), the first comprehensive database dedicated to antiviral peptides specifically targeting the #Ebola Virus (#EBOV). One of the projects I worked on collaboratively during my MTech final year. I am grateful to my team members Ananya Anurag Anand, Hon. D.Litt., Ayush Amod, DEBAYAN KARMAKAR, and Oshin Pal for their contributions, and to our PI, Dr. Sintu Samanta, for his invaluable guidance and support. 🧮 Why AEPDB? Despite the high fatality rates and significant global health impact of #Ebola virus disease (#EVD), a neglected tropical disease (#NTD), treatment options remain limited. While antibody-based therapies have shown promise, the urgent need for alternative and effective treatments is undeniable. #Antiviral peptides (#AVPs), a category of #antimicrobial peptides (#AMPs) known for their selectivity, specificity, and low toxicity, are emerging as potential game-changers in therapeutic development. 📈 A Step Towards Alternative Therapeutics AEPDB provides a structured platform to explore peptide-based treatments, supporting the development of new drugs against #EVD. It bridges a critical gap in infectious disease research and is a testament to the power of collaborative innovation in global health. 📄 Link to the paper: https://lnkd.in/g_5-5Jmz 🌐 Access AEPDB Here: https://lnkd.in/gPs9A-SD We are proud to contribute to the global fight against #Ebola, and we invite researchers and enthusiasts to leverage this resource to drive impactful discoveries. Thank you. #EbolaVirus #EbolaVirusDisease #EVD #NeglectedTropicalDisease #NTD #InfectiousDisease #AEPDB #AntiviralPeptides #AntimicrobialPeptides #PeptideBasedTherapeutics #AlternativeTherapeutics #GlobalHealth #DatabaseResearch #BiologicalDataScience #Bioinformatics #Innovation #Collaboration

I invite you to submit manuscripts to our research topic "Newer Initiatives in Detection, Drug Discovery and Therapeutic Management of Drug-Resistant Tuberculosis" in #Frontiers in Tropical Diseases. Further to the positive response from the authors, the manuscript submission deadline has been extended until July 31, 2024. We solicit original research articles, review reports, mini-reviews, case reports, and other article types suitable to the broader goal of this research topic. #tuberculosis #drugresistance #detection #drugdiscovery #therapy

What Enables Herpes Simplex Virus To Become Impervious to Drugs? Research pinpoints key to the cold sore virus’s ability to evade treatment, offering broader clues on antiviral drug resistance A 3D representation of a herpes simplex virus enzyme involved in viral replication. « What Enables Herpes Simplex Virus To Become Impervious to Drugs? Credit: Jonathan Abraham Lab/HMS Newswise — All organisms — from fungi to mammals — have the capacity to evolve and adapt to their environments. But viruses are master shapeshifters with an ability to mutate greater than any other organism. As a result, they can evade treatments or acquire resistance to once-effective antiviral medications. Is the Herpes Simplex Virus Becoming Impervious to Drugs? Working with herpes simplex virus (HSV), a new study led by Harvard Medical School researchers sheds light on one of the ways in which the virus becomes resistant to treatment, a problem that could be particularly challenging among people with compromised immune function, including those receiving immune-suppressive treatment and those born with immune deficiencies. Using a sophisticated imaging technique called cryogenic electron microscopy (cryo-EM), the researchers found t... #healthandwellness #HerpesSimplexVirus

20 March 2024 | Geneva The World Health Organization has just published recommendations on the use of a new class of diagnostic technologies: targeted next-generation sequencing (NGS) tests for the diagnosis of drug-resistant tuberculosis (TB) in the third edition of the Consolidated guidelines on tuberculosis. Module 3: Diagnosis. Rapid diagnostics for tuberculosis detection. The recommendations provide a novel approach for the rapid detection of drug resistance to new anti-TB drugs using the latest technologies. https://cutt.ly/fw244Kr3

University Of Liverpool Secures Major Funding Extension To Advance Revolutionary Long-Acting Therapeutic Technologies Link : https://lnkd.in/gmZjfgJ6 Unitaid has awarded over £6M of new funding to the University of Liverpool's LONGEVITY project, which aims to improve long-acting therapeutics for tuberculosis, malaria, and hepatitis C. The project, which began in 2020, has already achieved preclinical proof of concept for long-acting medications for tuberculosis and hepatitis C virus therapy. The primary motivation of LONGEVITY researchers is to ensure these therapeutics are easily accessible in low- and middle-income countries (LMICs). The extension funding of US $7.9 million will enable additional activities to address the specific needs and opportunities available for LMIC contexts, including pharmacometrics tools, optimizing programmatic outcomes through implementation research, exploring gaps in current therapies that could be mitigated with long-acting formulations, developing an informed understanding of manufacturing capability of generics manufacturers for established and emerging long-acting technologies, and establishing a community of practice for long-acting therapeutics in perinatal and paediatric health. #LongActing  therapeutics #HCV #TB .#longactingmedicine #longactingdurgs #CELT #drprajith

Detection of reduced sensitivity to a drug, even before that drug has been approved for use. It's a bit like falling in a race even before the starting gate has opened...😞 Genomic surveillance reveals a dengue 2 virus epidemic lineage with a marked decrease in sensitivity to Mosnodenvir. Abstract Dengue fever is the most important arbovirosis for public health, with more than 5 million cases worldwide in 2023. Mosnodenvir is the first anti-dengue compound with very high preclinical pan-serotype activity, currently undergoing phase 2 clinical evaluation. Here, by analyzing dengue virus (DENV) genomes from the 2023-2024 epidemic in the French Caribbean Islands, we show that they all exhibit mutation NS4B:V91A, previously associated with a marked decrease in sensitivity to mosnodenvir in vitro. Using antiviral activity tests on four clinical and reverse-genetic strains, we confirm a marked decrease in mosnodenvir sensitivity for DENV-2 ( > 1000 fold). Finally, combining phylogenetic analysis and experimental testing for resistance, we find that virus lineages with low sensitivity to mosnodenvir due to the V91A mutation likely emerged multiple times over the last 30 years in DENV-2 and DENV-3. These results call for increased genomic surveillance, in particular to track lineages with resistance mutations. These efforts should allow to better assess the activity profile of DENV treatments in development against circulating strains. https://lnkd.in/e3y8FZJD