Frontiers in drug discovery最新文献

{"title":"The case of the missing mouse—developing cystic fibrosis drugs without using animals","authors":"Lindsay J. Marshall, Kathleen M. Conlee","doi":"10.3389/fddsv.2024.1347246","DOIUrl":"https://doi.org/10.3389/fddsv.2024.1347246","url":null,"abstract":"Creating and developing new drugs can take decades, costs millions of dollars, requires untold human effort and usually, takes thousands of animal lives. Despite regulators professing confidence in non-animal approaches and guidance documents that permit submission of non-animal data, toxicity testing is routinely carried out in animals, employing rodents (invariably mice) and non-rodents. However, extensive preclinical testing in animals is still no guarantee that drugs will be safe and/or effective. In fact, more than nine out of every ten drugs that appear safe from animal trials will fail when tested in people, often due to unexplained toxicity or a lack of efficacy. This paper will describe recent advances in drug development where non-animal approaches have been used, to explore how and where these could be applied more widely to revolutionize the drug development pipeline and accelerate the creation of safe and effective medicines. As one case study, we look at the small molecule channel modifiers developed to address the consequences of the mutated chloride channel in the fatal genetic condition, cystic fibrosis. We then take a closer look at where drug development could be accelerated by focusing on innovative, human biology-based testing methods. Finally, we put forward recommendations, targeting all stakeholders, including the public, that will be needed to put this into practice and enable drug development to become more efficient - focusing on human-biology based testing and cutting out the middle-mouse.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"417 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140472973","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":"Multiparameter ranking of carbazoles for anti-trypanosome lead discovery.","authors":"Amrita Sharma, Carlos E Sanz-Rodriguez, Michael P Pollastri, Andrei Purmal, Kojo Mensa-Wilmot","doi":"10.3389/fddsv.2024.1430927","DOIUrl":"10.3389/fddsv.2024.1430927","url":null,"abstract":"<p><p>The criteria for the progression of hits in the discovery of leads for human African trypanosomiasis (HAT), a neglected disease caused by the microbial eukaryote <i>Trypanosoma brucei</i>, are not standardized. Hits are advanced upon meeting thresholds for drug-like molecules. Following those principles, pharmacokinetics (C_max and AUC_0-6h) and anti-trypanosome characteristics predicted the arrest of <i>T. brucei</i> proliferation in mice by three curaxins. Unexpectedly, while CBL0137 cured HAT in a mouse model, CBL0174 and CBL0187-structural analogs of CBL0137 with similar drug-like properties-failed to control <i>T. brucei</i> division. We here propose an alternative strategy that integrates physicochemical, metabolic, pharmacokinetic, pharmacodynamic, tissue distribution, and trypanocidality parameters into calculating a score for ranking compounds in hit-to-lead campaigns. Data from our studies of curaxins support the feasibility of this goal. Serum dropped the anti-trypanosome potency of CBL0174 and CBL0187 considerably. Delayed trypanocidal concentrations (DTC₂₅ and DTC₉₀) were used to study modes of curaxin actions in trypanosomes. Efficacy of CBL0137 in mice correlated with (i) a high AUC_0-6h: DTC₉₀ ratio, (ii) blocking of transferrin endocytosis, and (iii) the inhibition of protein synthesis. Hydroxylation of the carbazole prevented CBL0137 from inhibiting endocytosis of transferrin. The multiparametric score \"Curaxin HAT lead efficacy (CHLE)\" score was calculated using pharmacokinetic, physicochemical, metabolic, brain exposure, and pharmacodynamic data; CBL0137 was the highest scoring hit. Complementing these observations and predictive of performance of curaxins in mice, CBL0137, but not CBL0174 or CBL0187, was trypanocidal after the exposure of trypanosomes to AUC_0-6h amounts of the hits for 6 hours <i>in vitro</i>. We discuss a role for CHLE scores in ranking curaxins for anti-HAT lead discovery. The principles used to develop CHLE scores may be used to calculate new ones for other scaffolds during the discovery of leads for HAT or other infectious diseases.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"4 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927960/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694159","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":"Global proteomics insights for a novel small compound targeting the non-integrin Laminin Receptor in a macrophage cell model","authors":"Abigail Haffner, Manoel Figueiredo Neto, C. Umbaugh, Tiago J. P. Sobreira, T. Lescun, H. Sintim, M. Figueiredo","doi":"10.3389/fddsv.2023.1326736","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1326736","url":null,"abstract":"Introduction: Monocytes and macrophages are the first barrier of the innate immune system, which interact with agents causing osteoarthritis or other conditions, leading to the release of proinflammatory mediators that exacerbate inflammation.Methods: The aim of this study was to investigate the proteomic changes in THP-1 monocytes differentiated to macrophages, pre- or -post small compound treatments and in the presence or absence of a proinflammatory stimulus, Lipopolysaccharide (LPS). This study aimed to discover and isolate small compounds that mimic the interaction between Pigment derived growth factor (PEDF) and its 37/67 kDa Laminin receptor (LR) with potential anti-inflammatory activity.Results: Our results suggested that novel compounds targeting the LR-PEDF interface can be useful for modulating anti-inflammatory effects. Several compounds were selected based on in silico docking at the PEDF/LR interface and examined for their ability to reduce IL-1β expression in a macrophage cell model. Compound C3 showed the highest efficacy in reducing IL-1β expression in the presence of LPS proinflammatory stimulus. Proteomics analysis revealed that C3 treatment altered the global proteomic profile of THP-1 activated macrophages, affecting pathways such as MYC targets, oxidative phosphorylation, and mTORC1 signaling.Discussion: The analysis also highlighted the involvement of key regulators, including RPSA and MYC, and their interactions with other proteins such as ribosome proteins and cell cycle regulators. Furthermore, the downregulated proteome analysis revealed shared and unique pathways affected by the treatments, including processes related to actin cytoskeleton, translation, and the inflammatory response. Protein-protein interaction networks suggested the potential involvement of transcription factors like MYC and the interconnectedness of signaling pathways in mediating such as the effects of the treatments. Overall, these findings provide valuable insights into the potential anti-inflammatory activity and underlying mechanisms of compound C3, emphasizing its relevance for further investigation in the context of inflammatory conditions.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" 36","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138994748","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 mitochondrial metabolites and nucleic acids as an anti-inflammatory strategy","authors":"Yukun Min, Luke A. J. O’Neill","doi":"10.3389/fddsv.2023.1294454","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1294454","url":null,"abstract":"Mitochondrial metabolites and their derivatives have been the focus of recent efforts to develop new anti-inflammatory therapeutics. The widely used therapeutic agents dimethyl fumarate (DMF) and metformin have anti-inflammatory properties and have been shown to target metabolism. The mitochondrial metabolites succinate, itaconate, and fumarate have multiple immunomodulatory effects and present interesting therapeutic possibilities for immune and inflammatory diseases. Mitochondrial DNA and double-stranded RNA have also been shown to be highly inflammatory, acting via specific pattern recognition receptors (PRRs) such as cGAS and TLR9 for mitochondrial DNA, RIG-I, MDA5 for mitochondrial double stranded RNA, and TLR7 for mitochondrial single stranded RNA. These recent discoveries are changing our view of mitochondria suggesting that they are at the heart of multiple inflammatory diseases and provide opportunities for the development of new anti-inflammatory therapeutics.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"80 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138998724","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":"Case report: C-reactive protein apheresis in cardiogenic shock: case series from the C-reactive protein apheresis in acute myocardial infarction-registry","authors":"J. Torzewski, S. Mattecka, W. Ries, C. Garlichs, F. Heigl, J. Fiedler, A. Sheriff","doi":"10.3389/fddsv.2023.1286710","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1286710","url":null,"abstract":"C-reactive protein (CRP) apheresis may preserve myocardial tissue after acute myocardial infarction with delayed revascularization. Ten consecutive patients with cardiogenic shock were graded using the Society of Cardiovascular Angiography and Interventions shock classification and treated with CRP apheresis. All patients tolerated CRP apheresis well and were discharged in good clinical condition.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"16 24","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139010461","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":"Consensus docking aid to model the activity of an inhibitor of DNA methyltransferase 1 inspired by de novo design","authors":"Diana L. Prado-Romero, Alejandro Gómez-García, Raziel Cedillo-González, Hassan Villegas-Quintero, Juan F. Avellaneda-Tamayo, E. López-López, Fernanda I. Saldívar-González, Ana L. Chávez-Hernández, J. Medina‐Franco","doi":"10.3389/fddsv.2023.1261094","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1261094","url":null,"abstract":"The structure-activity relationships data available in public databases of inhibitors of DNA methyltransferases (DNMTs), families of epigenetic targets, plus the structural information of DNMT1, enables the development of a robust structure-based drug design strategy to study, at the molecular level, the activity of DNMTs inhibitors. In this study, we discuss a consensus molecular docking strategy to aid in explaining the activity of small molecules tested as inhibitors of DNMT1. The consensus docking approach, which was based on three validated docking algorithms of different designs, had an overall good agreement with the experimental enzymatic inhibition assays reported in the literature. The docking protocol was used to explain, at the molecular level, the activity profile of a novel DNMT1 inhibitor with a distinct chemical scaffold whose identification was inspired by de novo design and complemented with similarity searching.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"1 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138979883","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: Drug discovery for emerging and neglected tropical diseases: advances, challenges and perspectives","authors":"Laura Alcântara, Caio Franco, Nilmar Moretti, Denise Pilger","doi":"10.3389/fddsv.2023.1346042","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1346042","url":null,"abstract":"","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"51 25","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138588036","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":"Latest development of approved COVID-19 drugs and COVID-19 drugs undergoing late stage clinical trials","authors":"Bingru Feng, Kai Fu","doi":"10.3389/fddsv.2023.1304129","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1304129","url":null,"abstract":"As the world adapts to living with SARS-CoV-2, the continuous emergence of new variants has become a primary focus of current studies. In this review, we examined a range of available COVID-19 drugs, including FDA-regulated drugs and those undergoing late-stage clinical trials. Some FDA-regulated drugs, such as Veklury (remdesivir), Olumiant (baricitinib), and Actemra (tocilizumab), have garnered primary clinical status in treatment guidelines, supported by sufficient clinical evidence. Conversely, EUA-authorized therapies, such as some antiviral agents, have demonstrated lower efficacy due to the virus’s constant mutation. We also focused on COVID-19 drugs undergoing late-stage clinical trials, some of which have raised controversy in their administration, such as colchicine and corticosteroids, while others are worth exploring regarding their timing. Several ongoing multi-drug clinical trials are of particular interest, including the “MEDIC-LAUMC” trial that explores drug co-administration, and “ACTIV-2” and “ACTIV-3” trials that compare the effects of different drugs for non-hospitalized and hospitalized patients, respectively. These ongoing clinical trials at a late stage provide essential clinical evidence for future drug authorization and have the potential to provide better drug administration strategies for COVID-19 variants. We look forward to the continued exploration of drug co-administration, comprehensive clinical evidence for treatment, and the investigation of different potential drug utilization.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"128 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138621585","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":"Introduction to small molecule drug discovery and preclinical development","authors":"Michelle W. Y. Southey, Michael Brunavs","doi":"10.3389/fddsv.2023.1314077","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1314077","url":null,"abstract":"Over 90% of marketed drugs are small molecules, low molecular weight organic compounds that have been discovered, designed, and developed to prompt a specific biological process in the body. Examples include antibiotics (penicillin), analgesics (paracetamol) and synthetic hormones (corticosteroids). On average, it takes 10–15 years to develop a new medicine from initial discovery through to regulatory approval and the total cost is often in the billions. For every drug that makes it to the market, there are many more that do not, and it is the outlay associated with abortive efforts that accounts for most of this expense. The discovery of new drugs remains a significant challenge, involving teams of researchers from chemistry, biology, drug development, computer science and informatics. In this article we will discuss the key concepts and issues encountered in small molecule preclinical drug discovery and introduce some of the emerging technologies being developed to overcome current obstacles.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"49 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139206002","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":"HyBryte™ use in early-stage cutaneous T-cell lymphoma","authors":"B. Poligone, Carolina V Alexander-Savino, Ellen J. Kim, Aaron R. Mangold, Jennifer Desimone, Henry K. Wong, A. Rumage, O. Donini, Andrea M. Haulenbeek, Christopher J. Schaber, Richard Straube, C. Pullion, A. Rook","doi":"10.3389/fddsv.2023.1298453","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1298453","url":null,"abstract":"Cutaneous T-cell lymphoma (CTCL) is a rare type of non-Hodgkin lymphoma of the skin, where at later stages skin-homing malignant T-cells affect lymph nodes, blood, and visceral organs. Even though early CTCL does not affect survival, it can progress to more advanced stages of disease and have a significant effect on the quality of life of patients. Although expectant management is a treatment consideration in early disease stages, most patients cycle through different skin-directed therapies throughout their lifetime. It can become a challenge to manage the serious and accumulating risk of side effects of these therapies, including various skin cancers and skin damage. Adverse effects from topical therapies limit their long-term utility. Thus, there is an unmet need for well-characterized therapies that have a rapid onset of action and minimal long-term/cumulative side effect profile. Most recently, the results of a Phase 3 study of topical HyBryte™ as a potential treatment for CTCL demonstrated its efficacy and safety profile. This article summarizes what is known about HyBryte™, focuses on its mechanism of action, and highlights its effectiveness, safety, and tolerability in the context of other current FDA-approved topical therapies for CTCL.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"13 1-4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139233865","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}