Frontiers in drug discovery最新文献

{"title":"Optimization of a malachite green-pyrophosphatase assay for the Zika virus RNA-dependent RNA polymerase and preliminary identification of natural product modulators.","authors":"Vanessa Aitken, Anthony F T Moore, Manuel Terrazas-López, Salvador Rodarte, Eda Koculi","doi":"10.3389/fddsv.2026.1749327","DOIUrl":"10.3389/fddsv.2026.1749327","url":null,"abstract":"<p><p>The Zika virus (ZIKV) is an <i>Orthoflavivirus</i> linked to several neurological and developmental diseases, and it remains a significant global health concern for which no treatments or vaccines are currently available. In this study, we optimized the malachite green colorimetric assay, previously used to measure the RNA-dependent RNA polymerase (RdRp) activity of the hepatitis C and foot-and-mouth disease viruses, and applied this assay for the preliminary identification of the ZIKV RdRp modulators. RdRp is an enzyme essential for viral replication. Modulator screening was conducted using 204 compounds from the Natural Product Set IV of the National Cancer Institute Developmental Therapeutics Program. We identified two compounds, purpurogallin and digallic acid, as preliminary modulators of the ZIKV RdRp. Future studies will validate these preliminary hits using orthogonal assays, perform dose-response analyses, and elucidate their mechanisms of action.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"6 ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Angiotensin-Converting Enzyme in Cognitive Aging: Evidence from Preclinical and Clinical Studies.","authors":"Joshua Smith, Prakashkumar Dobariya, Tanvi R Kadam, Swati S More","doi":"10.3389/fddsv.2026.1855021","DOIUrl":"10.3389/fddsv.2026.1855021","url":null,"abstract":"<p><p>Angiotensin-Converting Enzyme (ACE, EC 3.4.15.1), also termed as kininase II or dipeptidyl carboxypeptidase I, is a crucial component of the Renin angiotensin system (RAS). ACE is extensively recognized for its role in the regulation of the cardiovascular system. Emerging evidence supports a neurobiological role of ACE, promoting investigations into its central functions responsible for the modulation of memory and cognitive function, particularly through the use of clinically approved ACE inhibitors (ACE-Is). This review comprehensively analyzes preclinical and clinical findings to date to evaluate the contribution of ACE to cognitive processes and discusses its potential as a therapeutic target for cognitive improvement. Mechanistically, ACE influences cognition through regulation of angiotensin II (Ang II) signaling, as well as modulating other neuropeptides such as substance P. These pathways intersect with processes implicated in cognitive decline, including oxidative stress, neuroinflammation, and cholinergic neurotransmission. Pre-clinical studies consistently demonstrate that ACE-Is confer neuroprotective effects by attenuating Ang II-mediated signaling, restoring redox and inflammatory balance, and improving synaptic plasticity. Clinical evidence provides partial support to these findings, although results remain heterogeneous. Variability in clinical outcomes appears to depend on factors such as patient age, baseline comorbidities, and central availability of the ACE-I. Collectively, this study highlights a non-canonical role of central ACE inhibition in modulating cognitive function, suggesting its promise as a therapeutic strategy for addressing age and disease-associated cognitive dysfunction. Future research should thus prioritize delineation of tissue-specific actions of ACE along with comprehensive examination of ACE genotype-drug interactions, and head- to-head comparison of centrally active ACE-Is with other RAS modulators for their nootropic potential.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"6 ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148221139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards human cardiac new approach methodologies (NAMs) to evaluate the combination of repolarization prolonging and shortening drugs: a pilot study.","authors":"Robert M Geiger, Carlos Serna, Bhavya Bhardwaj, Tromondae K Feaster, Ksenia Blinova","doi":"10.3389/fddsv.2025.1679626","DOIUrl":"10.3389/fddsv.2025.1679626","url":null,"abstract":"<p><strong>Background and purpose: </strong>Nonclinical human cardiac new approach methodologies (NAMs), including human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with multielectrode array (MEA) represent a highly predictive <i>in vitro</i> model for identifying drug-induced cardiac liabilities of individual drugs. Here, we extend the use of an <i>in vitro</i> cardiac NAM to evaluate the safety of a drug combination including moxifloxacin, an antibiotic, and QT prolonging drug, and cobicistat a pharmacokinetic booster shown to shorten repolarization <i>in vitro</i>.</p><p><strong>Methods: </strong>To generate the <i>in vitro</i> cardiac NAM, MEA coupled with hiPSC-CMs were cultured for 7-8 days. Cells were treated with moxifloxacin and cobicistat individually or in combination and changes in electrophysiology and contractility were evaluated.</p><p><strong>Results: </strong>The combination of cobicistat and moxifloxacin resulted in a concentration-dependent shortening of the corrected field potential duration (FPDcF) relative to both vehicle control and moxifloxacin alone. This effect was observed at near clinical Cmax concentrations of cobicistat and moxifloxacin. Evaluation of local extracellular action potentials (LEAP) revealed early afterdepolarizations (EADs) with supratherapeutic concentrations of moxifloxacin which were subsequently eliminated by the addition of cobicistat at therapeutic concentrations. Finally, the Comprehensive <i>in vitro</i> Proarrhythmia Assay (CiPA) Torsades de Pointes (TdP) risk tool categorized moxifloxacin treated cells as having a high or intermediate risk probability for TdP while concomitant treatment with cobicistat resulted in a low-risk categorization.</p><p><strong>Conclusion: </strong>We conclude that cobicistat can attenuate moxifloxacin induced FPDcF prolongation at clinically relevant concentrations <i>in vitro</i>. Taken together, this work provides a foundation to evaluate drug combinations <i>in vitro</i> to aid regulatory decision-making and reduce the dependence on animal studies.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"5 ","pages":"1679626"},"PeriodicalIF":5.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12690487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Across preclinical and clinical platforms, approved and investigational psychiatric drugs share pathways and associate with similar molecular functions.","authors":"Emily Su, Nico Matthew S Valencia, Jarod Le, Emily Liu, Jennifer L Wilson","doi":"10.3389/fddsv.2025.1686789","DOIUrl":"10.3389/fddsv.2025.1686789","url":null,"abstract":"<p><strong>Introduction: </strong>Translating findings from cell and animal models to the clinic is difficult because these systems insufficiently capture human disease biology. Computational approaches, notably pathways modeling, have overcome interspecies differences by mapping shared signaling pathways between species. We considered whether this approach could be generalized to bridge animal and virtual drug screening data to effects measured in patients. We emphasized translational psychiatry datasets because of the unmet need for effective therapies.</p><p><strong>Methods: </strong>We conducted three parallel analyses using published drug screening data in zebrafish, structure-function computational screening data, and clinically-reported efficacy data for experimental and approved antipsychotic drugs and predicted drug pathways using the PathFX algorithm.</p><p><strong>Results: </strong>Despite choosing screens developed for unique aspects of psychiatry and without careful curation of shared drugs, we found pathways associated with drugs that performed \"well\" across these distinct platforms-specifically, among drugs measured as favorable (expected to improve disease) or unfavorable (expected to aggravate disease) across screens, these drugs connected to distinct pathway proteins; however, these drugs are connected to similar protein families and shared Gene Ontology functional terms. By comparing screens, we discovered that favorable drugs may influence G-proteins, solute carrier family proteins, adrenoceptors, and steroid hydroxylase activity and that unfavorable drugs affect serotonin receptors and phosphodiesterase activity.</p><p><strong>Discussion: </strong>This suggests that predictive platforms could emphasize functional information as features that could overcome differences in distinct screening platforms to eventually improve translational approaches.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"5 ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13229565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148159100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transduction of hematopoietic stem and progenitor cells by an <i>MECP2</i> lentiviral vector improves Rett syndrome phenotypes.","authors":"Joseph S Anderson, Jill L Silverman, Alyse L Lodigiani, Camilla M Barbaduomo, Julie R Beegle","doi":"10.3389/fddsv.2025.1545391","DOIUrl":"10.3389/fddsv.2025.1545391","url":null,"abstract":"<p><strong>Introduction: </strong>Rett Syndrome is a genetic neurodevelopmental disorder caused by decreased levels of MeCP2. Due to mutations in the <i>MECP2</i> gene, insufficient MeCP2 protein levels lead to clinical phenotypes including the loss of normal movement, decreased communication, seizures, sleep disorders, and breathing problems. Currently there is no cure for Rett Syndrome and the only means to help patients is palliative care directed to their specific symptoms. Therefore, novel therapies need to be developed to alleviate disease phenotypes by restoring normal <i>MECP2</i> expression. An autologous hematopoietic stem cell and gene therapy approach for Rett syndrome may offer a benefit to affected patients by systemic delivery of functional MeCP2, including to affected neurons in the central nervous system.</p><p><strong>Methods: </strong>In our current experiments, we evaluated the therapeutic effect of <i>MECP2</i> lentiviral vector transduced human CD34+ hematopoietic stem and progenitor cells after transplantation into an immunodeficient mouse model of Rett syndrome.</p><p><strong>Results: </strong>We observed improvement of Rett syndrome-related phenotypes including the reversion toward normal motor abilities in an open field assay for total activity, horizontal activity, and vertical rearing activity, and an increased latency to fall in a rotarod assay. An increased level of MeCP2 protein was also observed in the brain tissue of transplanted mice.</p><p><strong>Discussion: </strong>By providing functional MeCP2 to affected cells, our results highlight the ability of this strategy to improve Rett syndrome phenotypes. These proof-of-concept studies demonstrate the potential use of a stem cell gene therapy approach as a novel treatment for Rett syndrome patients.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"5 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12393828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mimicking the immunosuppressive impact of fibroblasts in a 3D multicellular spheroid model","authors":"Melanie Grotz, Lieke van Gijzel, Peter Bitsch, Stefania C. Carrara, Harald Kolmar, Sakshi Garg","doi":"10.3389/fddsv.2024.1427407","DOIUrl":"https://doi.org/10.3389/fddsv.2024.1427407","url":null,"abstract":"Targeting the tumor microenvironment (TME) is an attractive strategy for cancer therapy, as tumor cells in vivo are surrounded by many different influential cell types, with complex interactions strongly affecting tumor progression and therapeutic outcome. Cancer-associated fibroblasts (CAFs) represent an abundant stromal cell type in the TME that modulate tumor development by exerting an immunosuppressive effect to influence effector immune cell activation. One promising target for TME-directed therapy is the CAF marker fibroblast activation protein-α (FAP). In this study, we employ a multicellular three-dimensional (3D) spheroid model, including tumor cells, fibroblast cells, and naïve T cells and could observe a protective effect of fibroblasts on tumor cells. Subsequently, we demonstrate that fibroblasts express FAP at differing expression levels in two-dimensional (2D) versus 3D cells. Lastly, we show that in a triple-culture of tumor cells, T cells and fibroblasts, the simultaneous assembly of fibroblasts using the high-affinity ligand oncoFAP with an engineered α-CD3-scFv-Fc-dextran-oncoFAP construct resulted in effective T cell activation to augment immunogenicity. Overall, this model can be routinely used for preclinical screening to study the effects of fibroblasts on the TME in vitro.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"21 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141801446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative therapeutics to control antimicrobial resistance: a general perspective","authors":"Biplab Singha, Vinayak Singh, Vijay Soni","doi":"10.3389/fddsv.2024.1385460","DOIUrl":"https://doi.org/10.3389/fddsv.2024.1385460","url":null,"abstract":"Antimicrobial Resistance (AMR) is a critical global health challenge, and in this review article, we examine the limitations of traditional therapeutic methods and the emerging role of alternative therapies. By examining the reasons behind the failure of conventional treatments, including the inadequacy of one-drug-one-enzyme approaches, the complex evolution of AMR, and the impact of drug biotransformation, we better understand why conventional treatments failed. Moreover, the review discusses several alternative therapies, including RNA-based treatments, aptamers, peptide-based therapies, phage therapy, and probiotics, discussing their applications, advantages, and limitations. Additionally, we discuss the obstacles to develop these therapies, including funding shortages, regulatory barriers, and public perception. This comprehensive analysis aims to provide insight into the future of AMR, emphasizing the need for innovative strategies and practical approaches.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141830491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: The boulder peptide symposium 2021 scientific update","authors":"Yvonne Angell, John Mayer, Rebecca Nofsinger, Waleed Danho","doi":"10.3389/fddsv.2024.1394489","DOIUrl":"https://doi.org/10.3389/fddsv.2024.1394489","url":null,"abstract":"","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"8 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140381394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular determinant deciphering of MIC-guided RND efflux substrates in E. coli","authors":"Johan Revol-Tissot, Gérard Boyer, Sandrine Alibert","doi":"10.3389/fddsv.2024.1326121","DOIUrl":"https://doi.org/10.3389/fddsv.2024.1326121","url":null,"abstract":"Antimicrobial resistance poses an urgent and formidable global public health threat. The escalation of bacterial multidrug resistance to antibiotics has the potential to become a leading cause of global mortality if there is no substantial improvement in antimicrobial development and therapy protocols. In light of this, it is imperative to identify the molecular determinants responsible for the reduced antibiotic activity associated with RND efflux pumps. This comprehensive study meticulously examines Minimum Inhibitory Concentration (MIC) data obtained from in vitro tests for various antibiotic families and non-active dye compounds, sourced from diverse literature references. The primary focus of this study is to assess the susceptibility of these agents to efflux-resistant Escherichia coli strains, integrating both MIC data and relevant physicochemical properties. The central objective is to unveil the specific substituents that significantly influence the uptake process mediated by the AcrAB-TolC efflux system. This exploration seeks to reveal the consequences of these substituents on pharmacodynamic responses, providing valuable insights into Structure-Activity Relationships. It is noteworthy that this analysis represents a pioneering effort, with prospective implications for RND efflux pump-producing strains. Ultimately, deciphering efflux markers is crucial to effectively mitigate the emergence of specific resistance and to better monitor the role of this primary resistance mechanism in Gram-negative bacteria, particularly as observed in clinical antibiotic therapy practice.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.frontiersin.org/articles/10.3389/fddsv.2024.1326121/pdf?isPublishedV2=False","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147905930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applying artificial intelligence to accelerate and de-risk antibody discovery","authors":"Astrid Musnier, Christophe Dumet, Saheli Mitra, Adrien Verdier, Raouf Keskes, Augustin Chassine, Yann Jullian, Mélanie Cortes, Yannick Corde, Z. Omahdi, Vincent Puard, T. Bourquard, A. Poupon","doi":"10.3389/fddsv.2024.1339697","DOIUrl":"https://doi.org/10.3389/fddsv.2024.1339697","url":null,"abstract":"As in all sectors of science and industry, artificial intelligence (AI) is meant to have a high impact in the discovery of antibodies in the coming years. Antibody discovery was traditionally conducted through a succession of experimental steps: animal immunization, screening of relevant clones, in vitro testing, affinity maturation, in vivo testing in animal models, then different steps of humanization and maturation generating the candidate that will be tested in clinical trials. This scheme suffers from different flaws, rendering the whole process very risky, with an attrition rate over 95%. The rise of in silico methods, among which AI, has been gradually proven to reliably guide different experimental steps with more robust processes. They are now capable of covering the whole discovery process. Amongst the players in this new field, the company MAbSilico proposes an in silico pipeline allowing to design antibody sequences in a few days, already humanized and optimized for affinity and developability, considerably de-risking and accelerating the discovery process.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"19 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140263618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}