Pub Date : 2024-02-12DOI: 10.3389/fntpr.2024.1353362
Tien T. Sword, Ghaeath S. K. Abbas, Constance B. Bailey
Peptide natural products have a wide range of useful applications as pesticides, veterinary agents, pharmaceuticals, and bioproducts. To discover new natural products, manipulate them for analog generation, and to harness the potential of these bioactive compounds for synthetic biology, it is necessary to develop robust methods for the expression of biosynthetic genes. Cell-free synthetic biology is emerging as an important complementary approach because it is highly desirable to express protein on a more rapid timescale and does not rely upon the genetic tractability of a strain thus improving the throughput of design-build-test-learn cycles. Additionally, generating metabolites outside the cell can overcome issues such as cellular toxicity which can hamper applications like antibiotic development. In this review, we focus on the cell-free production of peptide natural products generated by non-ribosomal peptide synthetase. Nonribsomal peptides are biosynthesized by non-ribosomal peptide synthetases which are large “mega” enzymes that provide specific challenges to heterologous expression. First, we summarize NRPSs and their corresponding peptide metabolites that are expressed in cell-free systems. With that, we discuss the requirements and challenges to express such large proteins in cell-free protein synthesis as well as host machineries that have been developed for cell-free protein synthesis that could be particularly relevant to generating non-ribosomal peptide metabolites in the future. The development of cell-free systems can then be used for prototyping to accelerate efforts towards engineered biosynthesis of these complex pathways.
{"title":"Cell-free protein synthesis for nonribosomal peptide synthetic biology","authors":"Tien T. Sword, Ghaeath S. K. Abbas, Constance B. Bailey","doi":"10.3389/fntpr.2024.1353362","DOIUrl":"https://doi.org/10.3389/fntpr.2024.1353362","url":null,"abstract":"Peptide natural products have a wide range of useful applications as pesticides, veterinary agents, pharmaceuticals, and bioproducts. To discover new natural products, manipulate them for analog generation, and to harness the potential of these bioactive compounds for synthetic biology, it is necessary to develop robust methods for the expression of biosynthetic genes. Cell-free synthetic biology is emerging as an important complementary approach because it is highly desirable to express protein on a more rapid timescale and does not rely upon the genetic tractability of a strain thus improving the throughput of design-build-test-learn cycles. Additionally, generating metabolites outside the cell can overcome issues such as cellular toxicity which can hamper applications like antibiotic development. In this review, we focus on the cell-free production of peptide natural products generated by non-ribosomal peptide synthetase. Nonribsomal peptides are biosynthesized by non-ribosomal peptide synthetases which are large “mega” enzymes that provide specific challenges to heterologous expression. First, we summarize NRPSs and their corresponding peptide metabolites that are expressed in cell-free systems. With that, we discuss the requirements and challenges to express such large proteins in cell-free protein synthesis as well as host machineries that have been developed for cell-free protein synthesis that could be particularly relevant to generating non-ribosomal peptide metabolites in the future. The development of cell-free systems can then be used for prototyping to accelerate efforts towards engineered biosynthesis of these complex pathways.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"81 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139783672","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 : 2024-02-12DOI: 10.3389/fntpr.2024.1353362
Tien T. Sword, Ghaeath S. K. Abbas, Constance B. Bailey
Peptide natural products have a wide range of useful applications as pesticides, veterinary agents, pharmaceuticals, and bioproducts. To discover new natural products, manipulate them for analog generation, and to harness the potential of these bioactive compounds for synthetic biology, it is necessary to develop robust methods for the expression of biosynthetic genes. Cell-free synthetic biology is emerging as an important complementary approach because it is highly desirable to express protein on a more rapid timescale and does not rely upon the genetic tractability of a strain thus improving the throughput of design-build-test-learn cycles. Additionally, generating metabolites outside the cell can overcome issues such as cellular toxicity which can hamper applications like antibiotic development. In this review, we focus on the cell-free production of peptide natural products generated by non-ribosomal peptide synthetase. Nonribsomal peptides are biosynthesized by non-ribosomal peptide synthetases which are large “mega” enzymes that provide specific challenges to heterologous expression. First, we summarize NRPSs and their corresponding peptide metabolites that are expressed in cell-free systems. With that, we discuss the requirements and challenges to express such large proteins in cell-free protein synthesis as well as host machineries that have been developed for cell-free protein synthesis that could be particularly relevant to generating non-ribosomal peptide metabolites in the future. The development of cell-free systems can then be used for prototyping to accelerate efforts towards engineered biosynthesis of these complex pathways.
{"title":"Cell-free protein synthesis for nonribosomal peptide synthetic biology","authors":"Tien T. Sword, Ghaeath S. K. Abbas, Constance B. Bailey","doi":"10.3389/fntpr.2024.1353362","DOIUrl":"https://doi.org/10.3389/fntpr.2024.1353362","url":null,"abstract":"Peptide natural products have a wide range of useful applications as pesticides, veterinary agents, pharmaceuticals, and bioproducts. To discover new natural products, manipulate them for analog generation, and to harness the potential of these bioactive compounds for synthetic biology, it is necessary to develop robust methods for the expression of biosynthetic genes. Cell-free synthetic biology is emerging as an important complementary approach because it is highly desirable to express protein on a more rapid timescale and does not rely upon the genetic tractability of a strain thus improving the throughput of design-build-test-learn cycles. Additionally, generating metabolites outside the cell can overcome issues such as cellular toxicity which can hamper applications like antibiotic development. In this review, we focus on the cell-free production of peptide natural products generated by non-ribosomal peptide synthetase. Nonribsomal peptides are biosynthesized by non-ribosomal peptide synthetases which are large “mega” enzymes that provide specific challenges to heterologous expression. First, we summarize NRPSs and their corresponding peptide metabolites that are expressed in cell-free systems. With that, we discuss the requirements and challenges to express such large proteins in cell-free protein synthesis as well as host machineries that have been developed for cell-free protein synthesis that could be particularly relevant to generating non-ribosomal peptide metabolites in the future. The development of cell-free systems can then be used for prototyping to accelerate efforts towards engineered biosynthesis of these complex pathways.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"58 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139843542","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 : 2024-01-15DOI: 10.3389/fntpr.2023.1309994
Elton L. Cao
Drug combination therapies have shown effective performance in treating cancer through increased efficacy and circumvention of drug resistance through synergy. Two avenues can be used to discover drug combinations: a novel approach that utilizes natural products compared with the textbook approach of utilizing existing chemotherapy drug combinations. Many natural products achieve efficacy due to synergistic interactions between the active ingredients. Therefore, the pharmacophore relationships in herbal compounds which synergize can potentially be applied to chemotherapy drugs to drive combination discovery. Machine learning approaches have been developed to identify drug combinations, especially deep neural networks (DNN), which have achieved state-of-the-art performance in many drug discovery tasks. Here, a drug protein interaction (DPI) prediction DNN, DeepDPI, was developed to employ DPI drug representations and achieved state-of-the-art performance using the DrugBank database. Two DNNs were also developed to predict novel drug combinations: DeepNPD, which predicts combinations in natural products, and DeepCombo, which predicts synergy in chemotherapy drugs, using the HERB and DrugCombDB databases respectively. An ensemble architecture enhanced with a novel similarity based weight adjustment (SBWA) approach was used and both models accurately predicted drug combinations for both known and unknown drugs. Lastly, a screening was conducted using each model where DeepNPD predicted combinations where drugs had similar targets, while DeepCombo predicted combinations where one agent potentiated the other, with both models’ predicted combinations investigated through a network-based analysis and identifying as a synergistic combinations in literature. DeepNPD notably identified Thioguanine and Hydroxyurea and DeepCombo discovered Vinblastine and Dasatinib as hits for potential new anticancer drug combinations. DeepNPD illustrates how natural products are a novel path where new drug combinations can be discovered.
{"title":"Natural product based anticancer drug combination discovery assisted by deep learning and network analysis","authors":"Elton L. Cao","doi":"10.3389/fntpr.2023.1309994","DOIUrl":"https://doi.org/10.3389/fntpr.2023.1309994","url":null,"abstract":"Drug combination therapies have shown effective performance in treating cancer through increased efficacy and circumvention of drug resistance through synergy. Two avenues can be used to discover drug combinations: a novel approach that utilizes natural products compared with the textbook approach of utilizing existing chemotherapy drug combinations. Many natural products achieve efficacy due to synergistic interactions between the active ingredients. Therefore, the pharmacophore relationships in herbal compounds which synergize can potentially be applied to chemotherapy drugs to drive combination discovery. Machine learning approaches have been developed to identify drug combinations, especially deep neural networks (DNN), which have achieved state-of-the-art performance in many drug discovery tasks. Here, a drug protein interaction (DPI) prediction DNN, DeepDPI, was developed to employ DPI drug representations and achieved state-of-the-art performance using the DrugBank database. Two DNNs were also developed to predict novel drug combinations: DeepNPD, which predicts combinations in natural products, and DeepCombo, which predicts synergy in chemotherapy drugs, using the HERB and DrugCombDB databases respectively. An ensemble architecture enhanced with a novel similarity based weight adjustment (SBWA) approach was used and both models accurately predicted drug combinations for both known and unknown drugs. Lastly, a screening was conducted using each model where DeepNPD predicted combinations where drugs had similar targets, while DeepCombo predicted combinations where one agent potentiated the other, with both models’ predicted combinations investigated through a network-based analysis and identifying as a synergistic combinations in literature. DeepNPD notably identified Thioguanine and Hydroxyurea and DeepCombo discovered Vinblastine and Dasatinib as hits for potential new anticancer drug combinations. DeepNPD illustrates how natural products are a novel path where new drug combinations can be discovered.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"120 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139529991","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 : 2024-01-05DOI: 10.3389/fntpr.2023.1338469
Diego Caprioglio, Valerio Fasano, Daniela Imperio, Martín J. Riveira
{"title":"Editorial: From chemistry to therapeutics: exploring the universe of cannabinoids and related meroterpenoids","authors":"Diego Caprioglio, Valerio Fasano, Daniela Imperio, Martín J. Riveira","doi":"10.3389/fntpr.2023.1338469","DOIUrl":"https://doi.org/10.3389/fntpr.2023.1338469","url":null,"abstract":"","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"69 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139381473","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 : 2024-01-04DOI: 10.3389/fntpr.2023.1332436
Celso R. de Oliveira, Zachary D. Ledvina, M. D. Leonard, Samuel O. Odoh, Craig D. Dodson, Christopher S. Jeffrey
A novel meroterpenoid cabagranin D was isolated with related neolignans cabagranins A–C from the leaves of Piper cabagranum (Costa Rica). Cabagranins A–C represent the first examples of 3,3′-neolignans isolated from the plant genus Piper, and the meroterpenoid cabagranin D displays an unprecedented Diels–Alder conjugate of an unsubstituted phenylpropenone and α-phellandrene. Details of the full structural elucidation of these compounds and a discussion of their potential biosynthetic relationships are presented.
从卡巴格兰胡椒（哥斯达黎加）的叶子中分离出了一种新的美拉德萜类化合物卡巴格兰素 D 和相关的新木质素卡巴格兰素 A-C。卡巴格拉宁 A-C 代表了从瓜蒌属植物中分离出的 3,3′-新木质素的第一个实例，卡巴格拉宁 D 显示出一种未被取代的苯基丙烯酮和 α-黄柏烯前所未有的 Diels-Alder 共轭物。本文详细介绍了这些化合物的完整结构，并讨论了它们潜在的生物合成关系。
{"title":"Isolation of new neolignans and an unusual meroterpenoid from Piper cabagranum","authors":"Celso R. de Oliveira, Zachary D. Ledvina, M. D. Leonard, Samuel O. Odoh, Craig D. Dodson, Christopher S. Jeffrey","doi":"10.3389/fntpr.2023.1332436","DOIUrl":"https://doi.org/10.3389/fntpr.2023.1332436","url":null,"abstract":"A novel meroterpenoid cabagranin D was isolated with related neolignans cabagranins A–C from the leaves of Piper cabagranum (Costa Rica). Cabagranins A–C represent the first examples of 3,3′-neolignans isolated from the plant genus Piper, and the meroterpenoid cabagranin D displays an unprecedented Diels–Alder conjugate of an unsubstituted phenylpropenone and α-phellandrene. Details of the full structural elucidation of these compounds and a discussion of their potential biosynthetic relationships are presented.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"75 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139387218","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 : 2024-01-03DOI: 10.3389/fntpr.2023.1321043
Ana C. F. de Albuquerque, Lucas Martorano, Fernando M. dos Santos
Covering: 2019 to 2023. Even with the advent of modern and complementary spectroscopy techniques, comprehensive characterization of natural product continues to represent an onerous and time-consuming task, being far away to become rather “routine”. Mainly due to their highly complex structures and small amount of isolated sample, in milligram or sub-milligram quantities, structural misassignment of natural products are still a recurrence theme in the modern literature. Since the seminal paper from Nicolau and Snider, in 2005, evaluating the various cases of reassignment of natural products, from the present era, in which NMR parameters calculations play such an important role in the structural elucidation of natural products, helping to uncover and ultimately revise the structure of previously reported compounds, a pertinent question arises: are we still chasing molecules that were never there? In this minireview, we intent to discuss the current state of computational NMR parameter calculations, with a particular focus on their application in the structural determination of natural products. Additionally, we have conducted a comprehensive survey of the literature spanning the years 2019–2023, in order to select and discuss recent noteworthy cases of incorrectly assigned structures that were revised through NMR calculations. Therefore, our main goal is to show what can be done through computational simulations of NMR parameters, currently user-friendly and easily implemented by non-expert users with basic skills in computational chemistry, before venturing into complex and time-consuming total synthesis projects. In conclusion, we anticipate a promising future for NMR parameter calculations, fueled by the ongoing development of user-friendly tools and the integration of artificial intelligence. The emergence of these advancements is poised to broaden the applications of NMR simulations, offering a more accessible and reliable means to address the persistent challenge of structural misassignments in natural product chemistry.
{"title":"Are we still chasing molecules that were never there? The role of quantum chemical simulations of NMR parameters in structural reassignment of natural products","authors":"Ana C. F. de Albuquerque, Lucas Martorano, Fernando M. dos Santos","doi":"10.3389/fntpr.2023.1321043","DOIUrl":"https://doi.org/10.3389/fntpr.2023.1321043","url":null,"abstract":"Covering: 2019 to 2023. Even with the advent of modern and complementary spectroscopy techniques, comprehensive characterization of natural product continues to represent an onerous and time-consuming task, being far away to become rather “routine”. Mainly due to their highly complex structures and small amount of isolated sample, in milligram or sub-milligram quantities, structural misassignment of natural products are still a recurrence theme in the modern literature. Since the seminal paper from Nicolau and Snider, in 2005, evaluating the various cases of reassignment of natural products, from the present era, in which NMR parameters calculations play such an important role in the structural elucidation of natural products, helping to uncover and ultimately revise the structure of previously reported compounds, a pertinent question arises: are we still chasing molecules that were never there? In this minireview, we intent to discuss the current state of computational NMR parameter calculations, with a particular focus on their application in the structural determination of natural products. Additionally, we have conducted a comprehensive survey of the literature spanning the years 2019–2023, in order to select and discuss recent noteworthy cases of incorrectly assigned structures that were revised through NMR calculations. Therefore, our main goal is to show what can be done through computational simulations of NMR parameters, currently user-friendly and easily implemented by non-expert users with basic skills in computational chemistry, before venturing into complex and time-consuming total synthesis projects. In conclusion, we anticipate a promising future for NMR parameter calculations, fueled by the ongoing development of user-friendly tools and the integration of artificial intelligence. The emergence of these advancements is poised to broaden the applications of NMR simulations, offering a more accessible and reliable means to address the persistent challenge of structural misassignments in natural product chemistry.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"42 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139451135","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 : 2023-12-21DOI: 10.3389/fntpr.2023.1302371
S. Aly, Abdullah M. M. Elbadry, Mohamed El-Shazly, Tsong-Long Hwang
Bone metabolism is characterized by an interplay between the deposition of bone matrix and mineralization and the resorption process. Osteoporosis is a form of systemic metabolic bone condition that causes bone density to decline and its microarchitecture to deteriorate, increasing the risk of fracture owing to fragility. The underlying cause of this clinical disease lies in the imbalance in bone remodeling, in which bone resorption by osteoclasts predominates over bone creation by osteoblasts. Natural remedies have long been used to cure and prevent osteoporosis. Genus Sophora of the Fabaceae family comprises about 69 species that showed many pharmacological effects, including bone health preservation. The activity of Sophora sp. in maintaining bone health was attributed to its antioxidant, regenerative, and anti-inflammatory qualities. In this review, we focused on the therapeutic properties of the extracts and isolated compounds from the genus Sophora in maintaining bone health, with special emphasis on the management of osteoporosis.
{"title":"Exploring the potential role of genus Sophora in the management of osteoporosis: a phytochemical and biological review","authors":"S. Aly, Abdullah M. M. Elbadry, Mohamed El-Shazly, Tsong-Long Hwang","doi":"10.3389/fntpr.2023.1302371","DOIUrl":"https://doi.org/10.3389/fntpr.2023.1302371","url":null,"abstract":"Bone metabolism is characterized by an interplay between the deposition of bone matrix and mineralization and the resorption process. Osteoporosis is a form of systemic metabolic bone condition that causes bone density to decline and its microarchitecture to deteriorate, increasing the risk of fracture owing to fragility. The underlying cause of this clinical disease lies in the imbalance in bone remodeling, in which bone resorption by osteoclasts predominates over bone creation by osteoblasts. Natural remedies have long been used to cure and prevent osteoporosis. Genus Sophora of the Fabaceae family comprises about 69 species that showed many pharmacological effects, including bone health preservation. The activity of Sophora sp. in maintaining bone health was attributed to its antioxidant, regenerative, and anti-inflammatory qualities. In this review, we focused on the therapeutic properties of the extracts and isolated compounds from the genus Sophora in maintaining bone health, with special emphasis on the management of osteoporosis.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138948317","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/fntpr.2023.1281061
Samantha L. S. Ellis, L. L. Nohara, Sarah Dada, Iryna Saranchova, Lonna Munro, Kyung‐Bok Choi, Emmanuel Garrovillas, C. Pfeifer, David E. Williams, Ping Cheng, Raymond J. Andersen, W. Jefferies
One of the primary obstacles in current cancer treatments lies in the extensive heterogeneity of genetic and epigenetic changes that occur in each arising tumour. However, an additional challenge persists, as certain types of cancer display shared immune deficiencies in the antigen processing machinery (APM). This includes the downregulation of human leukocyte antigen (HLA) class I molecules, which serve as peptide antigen receptors for T lymphocyte recognition that plays a crucial role in killing emerging tumours. Consequently, this contributes to immune escape in metastatic disease. Notably, current cell-based immunotherapies primarily focusing on T lymphocytes and the implementation of immune checkpoint inhibitor modalities have largely ignored the crucial task of reversing immune escape. This oversight may explain the limited success of these approaches becoming more effective cancer immunotherapies. Hence, there is a critical need to prioritize the discovery of new therapeutic candidates that can effectively address immune escape and synergize with evolving immunotherapy strategies. In this context, we identified curcuphenol in a cell-based screen from a library of marine extracts as a chemical entity that reverses the immune-escape phenotype of metastatic cancers. To advance these findings toward clinical efficacy, the present study describes the synthesis of analogues of naturally occurring curcuphenol with enhanced chemical properties and biological efficacy. Here we test the hypothesis that these curcuphenol analogues can evoke the power of the immune system to reduce the growth of metastatic disease in tumour bearing animals. Our findings indicate that these compounds effectively restore the expression of APM genes in metastatic tumours and inhibit the growth of highly invasive tumours in preclinical models, thereby counteracting the common immune evasion phenomenon observed in metastatic cancers. We conclude that cancer immunotherapies capable of boosting APM expression, hold great potential in maximizing the effectiveness of immune blockade inhibitors and eradicating invasive tumours.
目前治疗癌症的主要障碍之一在于，每种肿瘤的基因和表观遗传发生了广泛的异质性变化。然而，由于某些类型的癌症在抗原处理机制（APM）中表现出共同的免疫缺陷，因此还存在着另一个挑战。这包括人类白细胞抗原（HLA）Ⅰ类分子的下调，Ⅰ类分子是 T 淋巴细胞识别的肽抗原受体，在杀死新出现的肿瘤方面发挥着关键作用。因此，这导致了转移性疾病的免疫逃逸。值得注意的是，目前主要针对 T 淋巴细胞的细胞免疫疗法以及免疫检查点抑制剂模式的实施在很大程度上忽视了逆转免疫逃逸这一关键任务。这一疏忽可能是这些方法未能成功成为更有效的癌症免疫疗法的原因。因此，亟需优先发现能有效解决免疫逃逸并与不断发展的免疫疗法策略协同作用的新候选疗法。在此背景下，我们在基于细胞的筛选中从海洋提取物库中发现了姜黄酚（curcuphenol）这一化学实体，它能逆转转移性癌症的免疫逃逸表型。为了将这些发现推向临床疗效，本研究描述了具有更强化学特性和生物功效的天然姜黄酚类似物的合成过程。我们在此验证了一个假设，即这些姜黄酚类似物可以唤起免疫系统的力量，从而减少肿瘤动物体内转移性疾病的生长。我们的研究结果表明，在临床前模型中，这些化合物能有效恢复转移性肿瘤中 APM 基因的表达，抑制高侵袭性肿瘤的生长，从而抵消转移性癌症中常见的免疫逃避现象。我们的结论是，能够促进 APM 表达的癌症免疫疗法在最大限度地提高免疫阻断抑制剂的有效性和根除侵袭性肿瘤方面具有巨大潜力。
{"title":"Curcuphenols facilitate the immune driven attenuation of metastatic tumour growth","authors":"Samantha L. S. Ellis, L. L. Nohara, Sarah Dada, Iryna Saranchova, Lonna Munro, Kyung‐Bok Choi, Emmanuel Garrovillas, C. Pfeifer, David E. Williams, Ping Cheng, Raymond J. Andersen, W. Jefferies","doi":"10.3389/fntpr.2023.1281061","DOIUrl":"https://doi.org/10.3389/fntpr.2023.1281061","url":null,"abstract":"One of the primary obstacles in current cancer treatments lies in the extensive heterogeneity of genetic and epigenetic changes that occur in each arising tumour. However, an additional challenge persists, as certain types of cancer display shared immune deficiencies in the antigen processing machinery (APM). This includes the downregulation of human leukocyte antigen (HLA) class I molecules, which serve as peptide antigen receptors for T lymphocyte recognition that plays a crucial role in killing emerging tumours. Consequently, this contributes to immune escape in metastatic disease. Notably, current cell-based immunotherapies primarily focusing on T lymphocytes and the implementation of immune checkpoint inhibitor modalities have largely ignored the crucial task of reversing immune escape. This oversight may explain the limited success of these approaches becoming more effective cancer immunotherapies. Hence, there is a critical need to prioritize the discovery of new therapeutic candidates that can effectively address immune escape and synergize with evolving immunotherapy strategies. In this context, we identified curcuphenol in a cell-based screen from a library of marine extracts as a chemical entity that reverses the immune-escape phenotype of metastatic cancers. To advance these findings toward clinical efficacy, the present study describes the synthesis of analogues of naturally occurring curcuphenol with enhanced chemical properties and biological efficacy. Here we test the hypothesis that these curcuphenol analogues can evoke the power of the immune system to reduce the growth of metastatic disease in tumour bearing animals. Our findings indicate that these compounds effectively restore the expression of APM genes in metastatic tumours and inhibit the growth of highly invasive tumours in preclinical models, thereby counteracting the common immune evasion phenomenon observed in metastatic cancers. We conclude that cancer immunotherapies capable of boosting APM expression, hold great potential in maximizing the effectiveness of immune blockade inhibitors and eradicating invasive tumours.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"2 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138981176","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 : 2023-08-11DOI: 10.3389/fntpr.2023.1169182
Angie Bustos-Rangel, Jonathan Muñoz-Cabrera, L. Cuca, G. Arboleda, Mónica Ávila Murillo, A. Sandoval-Hernández
Abnormal production of reactive oxygen species (ROS) has been implicated in the physiopathology of neuronal cell death. Increased ROS levels are associated with exacerbated peptide aggregation, inflammation, and mitochondrial dysfunction, which facilitate the triggering of specific cell death pathways. Antioxidant molecules are potentially useful in the amelioration of neurodegeneration. In this regard, natural products are an invaluable source of antioxidants. Therefore, we investigate the antioxidant and neuroprotective activities of four Colombian angiosperm extracts. Antioxidant activity was evaluated by phytochemical assays using TLC techniques with Dragendorff reagent, ninhydrin, and chloranil in dioxane, NH3, Fast Blue, and FeCl3, together with bioautography using DPPH and β-carotene. In vitro neuroprotective activity, cell death, and ROS accumulation were evaluated by MTT and flow cytometry in the SH-SY5Y cell line exposed to paraquat and C2-ceramide. We found that Zanthoxylum rhoifolium Lam, Zanthoxylum martinicense, Nectandra membranacea, and Nectandra reticulata extracts have antioxidant activity higher than quercetin under a β-carotene bleaching assay and protect SH-SY5Y cells against paraquat and C2-ceramide associated with a reduction in ROS. In conclusion, these extracts have a strong neuroprotective potential, and the precise mechanism requires more evaluation.
{"title":"Neuroprotective and antioxidant activities of Colombian plants against paraquat and C2-ceramide exposure in SH-SY5Y cells","authors":"Angie Bustos-Rangel, Jonathan Muñoz-Cabrera, L. Cuca, G. Arboleda, Mónica Ávila Murillo, A. Sandoval-Hernández","doi":"10.3389/fntpr.2023.1169182","DOIUrl":"https://doi.org/10.3389/fntpr.2023.1169182","url":null,"abstract":"Abnormal production of reactive oxygen species (ROS) has been implicated in the physiopathology of neuronal cell death. Increased ROS levels are associated with exacerbated peptide aggregation, inflammation, and mitochondrial dysfunction, which facilitate the triggering of specific cell death pathways. Antioxidant molecules are potentially useful in the amelioration of neurodegeneration. In this regard, natural products are an invaluable source of antioxidants. Therefore, we investigate the antioxidant and neuroprotective activities of four Colombian angiosperm extracts. Antioxidant activity was evaluated by phytochemical assays using TLC techniques with Dragendorff reagent, ninhydrin, and chloranil in dioxane, NH3, Fast Blue, and FeCl3, together with bioautography using DPPH and β-carotene. In vitro neuroprotective activity, cell death, and ROS accumulation were evaluated by MTT and flow cytometry in the SH-SY5Y cell line exposed to paraquat and C2-ceramide. We found that Zanthoxylum rhoifolium Lam, Zanthoxylum martinicense, Nectandra membranacea, and Nectandra reticulata extracts have antioxidant activity higher than quercetin under a β-carotene bleaching assay and protect SH-SY5Y cells against paraquat and C2-ceramide associated with a reduction in ROS. In conclusion, these extracts have a strong neuroprotective potential, and the precise mechanism requires more evaluation.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"43 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124725168","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 : 2023-08-10DOI: 10.3389/fntpr.2023.1189619
C. L. G. Santos, K. O. Neves, Francinaldo A. Silva-Filho, B. R. Lima, E. Costa, A. D. L. Souza, H. Koolen, M. Pinheiro, F. Silva
Strychnos peckii (Loganiaceae) is an important active ingredient in curare poisons in the Amazon rainforest. Although previous studies have identified this species as a promising source of monoterpene indole alkaloids (MIAs), knowledge about other natural products is still scarce. Thus, to detect and guide the isolation of unprecedented bioactive compounds from the leaves of S. peckii, an untargeted high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) analysis was performed with the leaf aqueous extract. The HPLC-MS analysis allowed the detection of eleven compounds, including the alkaloids harman-3-carboxylic acid (5) and N,β-glucopyranosyl vincosamide (6), and the flavonoids quercetin 3-O-rhamnopyranoside (9) and kaempferol 3-O-rhamnopyranoside (10), all not previously reported in the Loganiaceae family. These compounds, along with strictosidine (3), 5-carboxystrictosidine (7), and desoxycordifoline (8) were isolated through modern chromatographic techniques and determined by using NMR spectroscopy in combination with MS. Overall, the untargeted HPLC-MS analysis proved to be a simple and effective approach to guide the isolation of substances not yet identified from S. peckii.
{"title":"LC-MS guided isolation of N,β-glucopyranosyl vincosamide and other compounds from the curare ingredient Strychnos peckii","authors":"C. L. G. Santos, K. O. Neves, Francinaldo A. Silva-Filho, B. R. Lima, E. Costa, A. D. L. Souza, H. Koolen, M. Pinheiro, F. Silva","doi":"10.3389/fntpr.2023.1189619","DOIUrl":"https://doi.org/10.3389/fntpr.2023.1189619","url":null,"abstract":"Strychnos peckii (Loganiaceae) is an important active ingredient in curare poisons in the Amazon rainforest. Although previous studies have identified this species as a promising source of monoterpene indole alkaloids (MIAs), knowledge about other natural products is still scarce. Thus, to detect and guide the isolation of unprecedented bioactive compounds from the leaves of S. peckii, an untargeted high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) analysis was performed with the leaf aqueous extract. The HPLC-MS analysis allowed the detection of eleven compounds, including the alkaloids harman-3-carboxylic acid (5) and N,β-glucopyranosyl vincosamide (6), and the flavonoids quercetin 3-O-rhamnopyranoside (9) and kaempferol 3-O-rhamnopyranoside (10), all not previously reported in the Loganiaceae family. These compounds, along with strictosidine (3), 5-carboxystrictosidine (7), and desoxycordifoline (8) were isolated through modern chromatographic techniques and determined by using NMR spectroscopy in combination with MS. Overall, the untargeted HPLC-MS analysis proved to be a simple and effective approach to guide the isolation of substances not yet identified from S. peckii.","PeriodicalId":159634,"journal":{"name":"Frontiers in Natural Products","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129642196","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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