Pub Date : 2023-12-01DOI: 10.3389/fddsv.2023.1304129
Bingru Feng, Kai Fu
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.
{"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":null,"pages":null},"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}
Pub Date : 2023-11-30DOI: 10.3389/fddsv.2023.1314077
Michelle W. Y. Southey, Michael Brunavs
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.
{"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":null,"pages":null},"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}
Pub Date : 2023-11-27DOI: 10.3389/fddsv.2023.1298453
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
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.
皮肤 T 细胞淋巴瘤（CTCL）是一种罕见的皮肤非霍奇金淋巴瘤，晚期皮肤上的恶性 T 细胞会影响淋巴结、血液和内脏器官。尽管早期的 CTCL 不会影响患者的生存，但它会发展到晚期，对患者的生活质量产生重大影响。虽然在疾病的早期阶段，预期管理是治疗的一个考虑因素，但大多数患者在其一生中会循环使用不同的皮肤导向疗法。管理这些疗法的副作用（包括各种皮肤癌和皮肤损伤）所带来的严重且不断累积的风险是一项挑战。局部疗法产生的不良反应限制了这些疗法的长期使用。因此，对于起效迅速、长期/累积副作用最小的特性良好的疗法的需求尚未得到满足。最近，一项关于外用 HyBryte™ 作为 CTCL 潜在疗法的 3 期研究结果表明了它的疗效和安全性。本文总结了目前对 HyBryte™ 的了解，重点介绍了其作用机制，并结合目前其他经 FDA 批准的 CTCL 外用疗法，强调了其有效性、安全性和耐受性。
{"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":null,"pages":null},"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}
Pub Date : 2023-11-23DOI: 10.3389/fddsv.2023.1335842
Agam Prasad Singh, Brijesh Rathi
{"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":null,"pages":null},"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}
Pub Date : 2023-11-22DOI: 10.3389/fddsv.2023.1298916
Theresa Neumann, Evelyn Hartung, Johanna Gellert, Lisa Weiss, Manon Weiske, Naomi Kast, Stephanie Gurka, Sophie Marinoff, Anika Jäkel, A. Danielczyk, Patrik Kehler
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.
{"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":null,"pages":null},"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}
Pub Date : 2023-11-21DOI: 10.3389/fddsv.2023.1249966
Benjamin M. Davies, F. Rutsch, Naren Vyavahare, Alexander Jones
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.
{"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":null,"pages":null},"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}
Pub Date : 2023-11-14DOI: 10.3389/fddsv.2023.1257698
Vinoth Rajendran, Keerthana Gurukkalot
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.
{"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":null,"pages":null},"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}
Pub Date : 2023-10-30DOI: 10.3389/fddsv.2023.1289314
Manisha Padmakumar, Steven Biesmans, Jorge S. Valadas, Jan R. Detrez, Gaëlle Gillet, Priscillia Bresler, Marie-Laure Clénet, Irena Kadiu
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.
{"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":null,"pages":null},"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}
Pub Date : 2023-09-18DOI: 10.3389/fddsv.2023.1254656
Adetutu Akinnuwesi, Samuel Egieyeh, Ruben Cloete
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.
{"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":null,"pages":null},"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}
Pub Date : 2023-09-05DOI: 10.3389/fddsv.2023.1249507
Hannah J. Gleneadie, Andrew Dimond, Amanda G. Fisher
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.
{"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":null,"pages":null},"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}
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