Pub Date : 2023-12-11DOI: 10.3389/fddsv.2023.1286710
J. Torzewski, S. Mattecka, W. Ries, C. Garlichs, F. Heigl, J. Fiedler, A. Sheriff
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.
{"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}
Pub Date : 2023-12-11DOI: 10.3389/fddsv.2023.1261094
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
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.
DNA 甲基转移酶（DNMTs）抑制剂、表观遗传靶标家族的结构-活性关系数据，加上 DNMT1 的结构信息，使得开发基于结构的药物设计策略成为可能，从而在分子水平上研究 DNMTs 抑制剂的活性。在本研究中，我们讨论了一种共识分子对接策略，以帮助解释作为 DNMT1 抑制剂测试的小分子的活性。该共识对接方法基于三种不同设计的验证对接算法，与文献报道的实验酶抑制测定结果总体上吻合良好。该对接方案在分子水平上解释了一种具有独特化学结构的新型 DNMT1 抑制剂的活性特征。
{"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}
Pub Date : 2023-12-08DOI: 10.3389/fddsv.2023.1346042
Laura Alcântara, Caio Franco, Nilmar Moretti, Denise Pilger
{"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}
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":"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}
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":"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}
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":"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}
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":"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}
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":"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}
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":"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}
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.
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