Frontiers in drug discovery最新文献

{"title":"Editorial: Advances in anti-malarial drug discovery","authors":"Agam Prasad Singh, Brijesh Rathi","doi":"10.3389/fddsv.2023.1335842","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1335842","url":null,"abstract":"","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"37 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139245289","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":"Targeting a cancer-specific LYPD3 glycoform for tumor therapy","authors":"Theresa Neumann, Evelyn Hartung, Johanna Gellert, Lisa Weiss, Manon Weiske, Naomi Kast, Stephanie Gurka, Sophie Marinoff, Anika Jäkel, A. Danielczyk, Patrik Kehler","doi":"10.3389/fddsv.2023.1298916","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1298916","url":null,"abstract":"Introduction: One of the most drastic changes in cancer is the altered glycosylation of proteins and lipids, giving rise to truncated O-glycans like the Thomsen Friedenreich (TF) or Thomsen nouvelle (Tn) antigen, which are almost absent on normal cells. Combined protein-carbohydrate epitopes comprising these specific glycans are ideal candidates for potent targeted therapies given their excellent tumor specificity and broad cancer expression.Methods and results: We have generated GT-002, a monoclonal antibody specifically targeting the epithelial glycoprotein LYPD3 only in the presence of a TF glycosylation. It does not cross-react with non-glycosylated LYPD3 or TF on other glycoproteins in ELISA and flow cytometry. GT-002 binds to various tumor cell lines and stains tumor tissues of different cancer indications including squamous cell carcinoma of the head and neck. The remarkable tumor specificity was confirmed in an immunohistochemistry study on a normal human tissue panel including several LYPD3-positive organs, where GT-002 elicited almost completely abolished normal tissue binding. Consequently, we observed markedly reduced binding of GT-002 to normal human tissues compared to Lupartumab, a conventional anti-LYPD3 antibody previously in clinical development as antibody-drug conjugate (BAY1129980). Neuraminidase treatment of healthy tissues, resulting in cleavage of sialic acid residues, re-established binding of GT-002 comparable to Lupartumab, showing that the GT-002 epitope is masked by sialic acid in normal cells.Discussion: We believe that GT-002 is a promising candidate for development of antibody-drug- and radio-conjugates as well as bispecific molecules and chimeric antigen receptor therapeutics and highlights the powerful potential of antibodies against combined protein-carbohydrate epitopes to reduce on-target/off-tumor cytotoxicity.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"33 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139247622","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":"Future treatments for the arteriopathy of ectopic calcification disorders","authors":"Benjamin M. Davies, F. Rutsch, Naren Vyavahare, Alexander Jones","doi":"10.3389/fddsv.2023.1249966","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1249966","url":null,"abstract":"Ectopic calcification disorders, including Generalized Arterial Calcification of Infancy (GACI) and Pseudoxanthoma Elasticum are rare but impactful on individuals, healthcare and society, with significant associated morbidity, mortality and healthcare costs. Available therapies are not curative and focus on reducing extracellular calcification to limit progression of the arteriopathy that is responsible for much of the morbidity and, in the case of GACI, significant early mortality (approximately 50% in infancy). In this article, current and emerging medical approaches are reviewed and critiqued, including dietary manipulation, phosphate binders, bisphosphonates, tissue nonspecific alkaline phosphatase inhibitors, ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) enzyme replacement, allele-specific therapies, gene therapies, and antibody targeted treatment. Available therapies may limit further arterial calcification, but in GACI in particular, significant calcification can be present at birth, contributing to high infant mortality. This highlights the need for new approaches that aim to reverse established calcification, rather than merely slow its progression. Recently, a promising new class of antibody-targeted nanoparticle therapeutics has emerged that can reverse established arterial calcification in animals, restoring arterial elasticity. In one realization, nanoparticles carry established chelators, such as ethylenediaminetetraacetic disodium acid, to sites of arterial damage, concentrating the impact of the chelator where it is needed and limiting off-target effects. Such drugs would complement existing and emerging therapies, such as ENPP1 enzyme replacement, that slow or prevent progression of calcification, by offering an opportunity to “reset” arterial health in ectopic calcification disorders. At present, ectopic calcification disorders are challenging to treat effectively and carry a high burden of morbidity and mortality, particularly in GACI. Recent drug developments offer good reason to be hopeful for a new era of effective therapeutics that may reverse established arterial disease as well as halt its progression.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139252745","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":"In vitro drug interaction of ionophores with artemisinin and chloroquine against Plasmodium falciparum 3D7 blood-stage infection","authors":"Vinoth Rajendran, Keerthana Gurukkalot","doi":"10.3389/fddsv.2023.1257698","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1257698","url":null,"abstract":"The prevalence of clinical resistance of P. falciparum towards artemisinin and its partner drugs has significantly hampered malarial chemotherapy. To circumvent this situation, identifying a new class of partner drugs with significant anti-malarial efficacy and multi-stage activity can slow the development of resistance. This study demonstrates the potential interactions of carboxylic ionophores such as monensin (MON), maduramicin (MAD) or salinomycin (SAL) with standard antimalarial drugs artemisinin (ART) or chloroquine (CQ). The in vitro drug interactions were studied in P. falciparum 3D7 strain by a growth inhibition SYBR green 1 assay. The asynchronized parasites were exposed for 48 h in the presence of varying proportions of two drug concentrations using the modified fixed-ratio isobologram method. We determined the growth inhibition response and the sums of the fractional inhibitory concentrations (ΣFICs) of the following drug combinations (4:1, 3:2, 2:3, 1:4) and (1:1, 1:3, 3:1) were calculated for 50% inhibitory concentrations (IC 50 s). Combining artemisinin with monensin, maduramicin, or salinomycin showed significant additive interaction. A combination of chloroquine with monensin, maduramicin, or salinomycin showed slight synergism to additive interaction. None of the drug combinations displayed an antagonistic effect indicating ionophores usage in combination therapy to treat drug-resistant malarial infections.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"43 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134992070","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":"An improved method for large scale generation and high-throughput functional characterization of human iPSC-derived microglia","authors":"Manisha Padmakumar, Steven Biesmans, Jorge S. Valadas, Jan R. Detrez, Gaëlle Gillet, Priscillia Bresler, Marie-Laure Clénet, Irena Kadiu","doi":"10.3389/fddsv.2023.1289314","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1289314","url":null,"abstract":"Neuroscience drug discovery has faced significant challenges due to restricted access to relevant human cell models and limited translatability of existing preclinical findings to human pathophysiology. Induced pluripotent stem cells (iPSCs) have emerged as a promising solution, offering the potential to generate patient-specific cell types, including in the recent years, iPSC-derived microglia (iMGL). Current methods rely on complex and time-consuming differentiation procedures, leading to considerable batch-to-batch variability consequently hindering the establishment of standardized and reproducible high-throughput functional screening approaches. Addressing these challenges is critical in ensuring the generation of homogenous iMGL populations with consistent functional properties. In this study we describe an improved high-yield protocol for generating iMGL, which allows for increased reproducibility and flexibility in the execution of high-throughput functional screens. We introduce a two-step process in embryoid bodie (EB) maintenance and a stop point allowing for cryopreservation at the hematopoietic progenitor cell (iHPC) stages. Furthermore, we demonstrate inter-operator robustness of this modified protocol in a range of high-throughput functional assays including phagocytosis, lysosomal acidification, chemotaxis, and cytokine release. Our study underscores the importance of quality control checks at various stages of iPSC-differentiation and functional assay set up, highlighting novel workarounds to the existing challenges such as limited yield, flexibility, and reproducibility, all critical in drug discovery.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"110 ","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136067492","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":"State-of-the-art strategies to prioritize Mycobacterium tuberculosis drug targets for drug discovery using a subtractive genomics approach","authors":"Adetutu Akinnuwesi, Samuel Egieyeh, Ruben Cloete","doi":"10.3389/fddsv.2023.1254656","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1254656","url":null,"abstract":"Tuberculosis remains one of the causes of death from a single infectious bacterium. The inappropriate use of antibiotics and patients’ non-compliance among other factors drive the emergence of drug-resistant tuberculosis. Multidrug-resistant and extensively drug-resistant strains of tuberculosis pose significant challenges to current treatment regimens, as their reduced efficacy against these strains limits successful patient outcomes. Furthermore, the limited effectiveness and associated toxicity of second-line drugs further compound the issue. Moreover, the scarcity of novel pharmacological targets and the subsequent decline in the number of anti-TB compounds in the drug development pipeline has further hindered the emergence of new therapies. As a result, researchers need to develop innovative approaches to identify potential new anti-TB drugs. The evolution of technology and the breakthrough in omics data allow the use of computational biology approaches, for example, metabolomic analysis to uncover pharmacological targets for structured-based drug design. The role of metabolism in pathogen development, growth, survival, and infection has been established. Therefore, this review focuses on the M. tb metabolic network as a hub for novel target identification and highlights a step-by-step subtractive genomics approach for target prioritization.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135203072","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":"Harnessing bioluminescence for drug discovery and epigenetic research","authors":"Hannah J. Gleneadie, Andrew Dimond, Amanda G. Fisher","doi":"10.3389/fddsv.2023.1249507","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1249507","url":null,"abstract":"The naturally occurring phenomenon of bioluminescence has intrigued on-lookers for decades and is now being developed as a powerful tool for medical research and preclinical imaging. Luciferase enzymes emit light upon substrate encounter, enabling their activity to be visualised and dynamically tracked. By inserting luciferase genes into specific sites in the genome, it is possible to engineer reporters to monitor gene expression in its native context, and to detect epigenetic change in vivo. Endogenous bioluminescent reporters provide a highly sensitive, quantitative read-out of gene expression that is both well suited to longitudinal studies and can be adapted for high-throughput drug screens. In this article we outline some of the applications and benefits of bioluminescent reporters for epigenetic research, with a particular focus on revealing new therapeutic options for treating genetic and epigenetic disorders.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44486379","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":"Novel mesothelin antibodies enable crystallography of the intact mesothelin ectodomain and engineering of potent, T cell-engaging bispecific therapeutics","authors":"I-Yen Lin, P. Rupert, K. Pilat, Raymond O. Ruff, D. Friend, M. Chan, Midori Clarke, B. Hoffstrom, Jane Carter, S. Meshinchi, A. Bandaranayake, C. Mehlin, James M. Olson, R. Strong, C. Correnti","doi":"10.3389/fddsv.2023.1216516","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1216516","url":null,"abstract":"Mesothelin is a glypiated, cell-surface glycoprotein expressed at low levels on normal mesothelium but overexpressed by many cancers. Implicated in cell adhesion and multiple signaling pathways, mesothelin’s precise biological function and overall structure remain undefined. Antibodies targeting mesothelin have been engineered into immunotoxins, antibody-drug conjugates, CAR-T cells, or bispecific T cell engagers as candidate therapeutics but most face challenges, including binding epitopes that are not optimal for selected modalities. Here we describe the isolation and characterization of a novel anti-mesothelin antibody, 1A12, including crystallographic mapping of the 1A12 epitope in relation to other antibodies (amatuximab, anetumab). 1A12 possesses uniquely favorable properties, including a membrane-proximal epitope, and enabled structure determination of the complete mesothelin ectodomain. We incorporated 1A12 into two different bispecific T cell engaging architectures with various anti-CD3 co-targeting elements as candidate therapeutics, demonstrating in vitro functionality and potency.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45451457","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":"The importance of good practices and false hits for QSAR-driven virtual screening real application: a SARS-CoV-2 main protease (Mpro) case study","authors":"M. Serafim, S. Q. Pantaleão, E. B. da Silva, J. McKerrow, A. O’Donoghue, B. E. Mota, K. M. Honório, V. Maltarollo","doi":"10.3389/fddsv.2023.1237655","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1237655","url":null,"abstract":"Computer-Aided Drug Design (CADD) approaches, such as those employing quantitative structure-activity relationship (QSAR) methods, are known for their ability to uncover novel data from large databases. These approaches can help alleviate the lack of biological and chemical data, but some predictions do not generate sufficient positive information to be useful for biological screenings. QSAR models are often employed to explain biological data of chemicals and to design new chemicals based on their predictions. In this review, we discuss the importance of data set size with a focus on false hits for QSAR approaches. We assess the challenges and reliability of an initial in silico strategy for the virtual screening of bioactive molecules. Lastly, we present a case study reporting a combination approach of hologram-based quantitative structure-activity relationship (HQSAR) models and random forest-based QSAR (RF-QSAR), based on the 3D structures of 25 synthetic SARS-CoV-2 Mpro inhibitors, to virtually screen new compounds for potential inhibitors of enzyme activity. In this study, optimal models were selected and employed to predict Mpro inhibitors from the database Brazilian Compound Library (BraCoLi). Twenty-four compounds were then assessed against SARS-CoV-2 Mpro at 10 µM. At the time of this study (March 2021), the availability of varied and different Mpro inhibitors that were reported definitely affected the reliability of our work. Since no hits were obtained, the data set size, parameters employed, external validations, as well as the applicability domain (AD) could be considered regarding false hits data contribution, aiming to enhance the design and discovery of new bioactive molecules.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46875160","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":"9-PAHSA displays a weak anti-inflammatory potential mediated by specific antagonism of chemokine G protein-coupled receptors","authors":"P. Wohlfart, Mounir Chehtane, E. Luna, R. Mehta, M. Korn, A. Konkar, U. Schwahn, S. Petry, N. Tennagels, M. Bielohuby","doi":"10.3389/fddsv.2023.1138461","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1138461","url":null,"abstract":"Introduction: 9-PAHSA belongs to a class of endogenous mammalian bioactive lipids, fatty acid esters of hydroxy fatty acids (FAHFA), that are present in circulation at nanomolar concentrations in mice and humans. Published preclinical data suggest beneficial effects of 9-PAHSA treatment on glucose metabolism as well as modulation of immune function. However, receptor molecules with high affinity towards these lipids have not been identified so far.Methods: In a broad screen of a panel of G protein-coupled receptors (GPCRs) we discovered that 9-PAHSA displays antagonist activity with an IC50 in the micromolar range on selected chemokine receptors, namely, CCR6, CCR7, CXCR4, and CXCR5. The potential immunomodulatory activities in a human cellular model of innate immunity were then investigated.Results and discussion: In our in vitro experiments, a weak anti-inflammatory potential for high concentrations of 9-PAHSA (10–100 µM) could be detected, as treatment reduced the LPS-induced secretion of certain chemokines, such as CXCL10, MIP-1 beta and MCP. Regarding metabolic effects, we re-investigated 9-PAHSA on glucose metabolism and insulin sensitivity in vitro and in mice confirming conclusions from our earlier study that FAHFAs lack glucoregulatory activity following an acute treatment. In conclusion, the specific interactions with a subset of chemokine receptors may contribute to weak anti-inflammatory properties of 9-PAHSA, but further studies are needed to confirm its in anti-inflammatory potential in vivo.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47300131","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}