Medicine in Drug Discovery最新文献_第10页

The folding and misfolding mechanisms of multidomain proteins 多结构域蛋白的折叠和错误折叠机制

Medicine in Drug Discovery Pub Date : 2022-06-01 DOI: 10.1016/j.medidd.2022.100126

Yanfang Lu, Bin Zhu, Qianqian Li, Jiang Du, Tao Chen

{"title":"The folding and misfolding mechanisms of multidomain proteins","authors":"Yanfang Lu, Bin Zhu, Qianqian Li, Jiang Du, Tao Chen","doi":"10.1016/j.medidd.2022.100126","DOIUrl":"10.1016/j.medidd.2022.100126","url":null,"abstract":"<div><p>The reliable folding of proteins is essential for their biological activities, while misfolding may lead to severe diseases, such as Alzheimer’s disease. However, our current knowledge of protein folding arises mainly from studies on small, single-domain proteins rather than multidomain proteins, although the latter make up most of proteins in the cell. Due to complex topological structures and potential interdomain interactions, the refolding of many multidomain proteins often passes through long-lived partially folded intermediates and exhibits complex kinetics. Here, we survey recent progress in understanding the folding and misfolding of multidomain proteins <em>in vitro</em>, with particular reference to theoretical aspects, and briefly summarize the researches on how ribosome regulates folding kinetics of nascent chains during translation <em>in vivo</em>, such as the environmental effects of the ribosome, translation rate effects, and self-interactions effects of polypeptide chain. In addition to these important advances, many questions are still waiting for answer, including: Can a purely structure-based model capture the complex folding kinetics of some multidomain proteins caused by the significant energetic frustration? Is the energy landscape of cotranslational folding still perfectly funnel-like? Are the observed principles that ribosome promotes the proper folding of proteins universal? To what extent does cotranslational folding affect nonnative interactions? Collectively, to address these issues, further innovation and improvement on both experimental techniques and the computational models are in great demand.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"14 ","pages":"Article 100126"},"PeriodicalIF":0.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098622000070/pdfft?md5=3038c38de62bfd62c9e8e4e88980298d&pid=1-s2.0-S2590098622000070-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42525934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

The Delta variant mutations in the receptor binding domain of SARS-CoV-2 show enhanced electrostatic interactions with the ACE2 SARS-CoV-2受体结合域的δ变异突变与ACE2的静电相互作用增强

Medicine in Drug Discovery Pub Date : 2022-03-01 DOI: 10.1016/j.medidd.2021.100114

Shaimaa S. Goher , Fedaa Ali , Muhamed Amin

引用次数: 28

KILLING THE CURE? Is targeting LIF to treat pancreatic cancer a dangerous case of mistaken identity? 杀死治愈方法?靶向LIF治疗胰腺癌是一个误认的危险案例吗?

Medicine in Drug Discovery Pub Date : 2022-03-01 DOI: 10.1016/j.medidd.2021.100112

Su Metcalfe

{"title":"KILLING THE CURE? Is targeting LIF to treat pancreatic cancer a dangerous case of mistaken identity?","authors":"Su Metcalfe","doi":"10.1016/j.medidd.2021.100112","DOIUrl":"10.1016/j.medidd.2021.100112","url":null,"abstract":"<div><p>Leukaemia Inhibitory Factor (LIF) is a stem cell growth factor critical to health. LIF belongs to the IL-6 family of cytokines but LIF-signalling is unique and qualified by its cell surface receptor, LIF-R. As a strategy to treat pancreatic cancer, Hunter et al. [1] report an engineered therapeutic LIF-Trap (soluble LIF-R) to deplete human LIF. Whilst applauding the engineering success of the LIF-Trap, I argue a case of mistaken identity. Is it LIF, or IL-6, promoting tumour progression? The rationale is based on the earlier work of the same group reported by Shi et al. [2] who have already generated a specific anti-LIF antibody for the same therapeutic purpose as the LIF-Trap: this antibody has since been acquired by a leading pharmaceutical company.</p></div><div><h3>CRITIQUE</h3><p>There are two major issues with the Hunter and Shi publications. <u>First Safety</u> – Hunter claims safety of their LIF-Trap despite extensive data arguing to the contrary: thus removal of LIF signalling risks pathogenic effects in multiple systems. <u>Second Scientific</u> – the group fail to take into account LIF biology, where mode of action places IL-6, rather than LIF, as candidate for driver of tumour progression. Importantly, clinical data suggests LIF-signalling functions as a tumour <em>suppressor</em> in pancreatic cancer [3], raising the question – would removal of LIF-signalling be counter-indicated in cancer?</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"13 ","pages":"Article 100112"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098621000336/pdfft?md5=cf7c2f5da35c42631892c7882b9341c4&pid=1-s2.0-S2590098621000336-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48406441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Blood cells as supercarrier systems for advanced drug delivery 血细胞作为高级药物输送的超级载体系统

Medicine in Drug Discovery Pub Date : 2022-03-01 DOI: 10.1016/j.medidd.2021.100119

Shuo Wang , Keqin Han , Shuhao Ma , Xiaojing Qi , Ling Guo , Xuejin Li

{"title":"Blood cells as supercarrier systems for advanced drug delivery","authors":"Shuo Wang , Keqin Han , Shuhao Ma , Xiaojing Qi , Ling Guo , Xuejin Li","doi":"10.1016/j.medidd.2021.100119","DOIUrl":"10.1016/j.medidd.2021.100119","url":null,"abstract":"<div><p>In recent years, drug delivery has emerged as a more and more popular drug administration means for the improvement of pharmacokinetics, minimization of side effects, and enhancement of clinical outcomes. However, rapid clearance from the blood flow by immune systems limits the performance of drugs injected into the blood circulation. Thus, a new avenue for drug delivery systems by using the blood cells has drawn increasing attention. Blood cells can protect the drugs from macrophage uptake, prolong their circulation time, and improve their biocompatibility and stability. Here, we review recent advances in the developments and applications of numerous blood cell-based drug delivery systems and those inspired by blood cells. We highlight examples of vascular drug delivery using carriers red blood cells, white blood cells as well as platelets. We expect that this review will provide a jumping-off point or an inspiration for further investigation in this area.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"13 ","pages":"Article 100119"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098621000403/pdfft?md5=87988d7eaa6d5c1142a0c026d2fb0e89&pid=1-s2.0-S2590098621000403-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48298324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 10

Probes and techniques used in active and the hypoxia-based dormant state of an antitubercular drug screening assay 用于活性和低氧休眠状态的抗结核药物筛选试验的探针和技术

Medicine in Drug Discovery Pub Date : 2022-03-01 DOI: 10.1016/j.medidd.2021.100115

Amar Yeware , Shamim Akhtar , Dhiman Sarkar

{"title":"Probes and techniques used in active and the hypoxia-based dormant state of an antitubercular drug screening assay","authors":"Amar Yeware , Shamim Akhtar , Dhiman Sarkar","doi":"10.1016/j.medidd.2021.100115","DOIUrl":"10.1016/j.medidd.2021.100115","url":null,"abstract":"<div><p>Current antitubercular drug therapy requires more than six months and is unable to kill latent or dormant forms of tuberculosis. Thus, it is a need of new drug therapy to fight against dormant tuberculosis. However, the major obstacle in the development of novel drugs for dormant tuberculosis is the lack of relevant screening systems and using reliable probes to measure growth inhibition. Until now, several probes used in active state assays are significantly determining the inhibitory effect against the active state of mycobacteria. The dormant condition assays are based on hypoxia-derived dormancy which include resazurin reduction assay, nitrite reductase assay, XTT reduction menadione assay and low oxygen recovery assay. Major probes used in those assays are colorimetric/fluorescent dyes, enzymatic activity, and reporter genes include luciferase and fluorescent proteins. Although these dormant assays are based on hypoxia-induced features and difficult to maintain for a longer duration. Also, they further complicated by growth detection and pursuit of high throughput screening criteria. Here we reviewed complications of probes and assay techniques used for anti<em>-</em>dormant drug screening programs of tuberculosis. This will provide the knowledge to design better alternative drug screening method for the anti-dormant form of tuberculosis.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"13 ","pages":"Article 100115"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098621000361/pdfft?md5=46d2d8229fd325af54c662f87750c7c9&pid=1-s2.0-S2590098621000361-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45237007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Brain metastases: Nanomedicine-boosted diagnosis and treatment 脑转移:纳米医学促进的诊断和治疗

Medicine in Drug Discovery Pub Date : 2022-03-01 DOI: 10.1016/j.medidd.2021.100111

Liang Han

引用次数: 0

Amplifying antitumor T cell immunity with versatile drug delivery systems for personalized cancer immunotherapy 增强抗肿瘤T细胞免疫与多功能药物输送系统的个性化癌症免疫治疗

Medicine in Drug Discovery Pub Date : 2022-03-01 DOI: 10.1016/j.medidd.2021.100116

Ping Xiao , Yaping Li , Dangge Wang

{"title":"Amplifying antitumor T cell immunity with versatile drug delivery systems for personalized cancer immunotherapy","authors":"Ping Xiao , Yaping Li , Dangge Wang","doi":"10.1016/j.medidd.2021.100116","DOIUrl":"10.1016/j.medidd.2021.100116","url":null,"abstract":"<div><p>Cancer immunotherapy is becoming an important option for treating patients with cancer in clinic. Given the heterogeneity of tumors between individuals, personalized cancer immunotherapy is the most promising one. Tremendous progresses have been achieved to initialize personalized immunity in patients through delivering tumor-derived neoantigens or adoptive transfer of engineered immune cells such as T cells and nature killer cells. However, the objective response rate and therapeutic efficiency of most personalized immunotherapies are hampered by the biophysical barriers against drug delivery and the limited infiltration of engineered cells into solid tumors. To overcome these limitations, versatile drug delivery systems have been developed to deliver personalized tumor antigens to target and promote intratumoral infiltration of lymphocytes, thus generating a local immunogenic niche to induce potent and durable antitumor immune responses. In this review, we will summarize the major barriers for efficient personalized immunization, highlight our lab and several other groups’ efforts in versatile drug delivery systems for delivering tumor-specific antigens, autologous tumor cell-derived antigens and combining with adoptive transfer of engineered immune cells. At the end of this review, we also look forward to the future development of drug delivery system-based personalized immunotherapy and its challenges for clinical translation.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"13 ","pages":"Article 100116"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098621000373/pdfft?md5=a76d03cb56eed804513ae049e510dc65&pid=1-s2.0-S2590098621000373-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44845413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Wnt/β-catenin signaling pathway in lung cancer 肺癌中的Wnt/β-catenin信号通路

Medicine in Drug Discovery Pub Date : 2022-03-01 DOI: 10.1016/j.medidd.2021.100113

Wenhua Zhu , Heng Wang , Di Zhu

引用次数: 0

Rapidly separable microneedle patches for controlled release of therapeutics for long-acting therapies 用于长效治疗药物控释的快速可分离微针贴片

Medicine in Drug Discovery Pub Date : 2022-03-01 DOI: 10.1016/j.medidd.2021.100118

Chenyuan Wang , Xue Jiang , Yongnian Zeng , Richard N. Terry , Wei Li

{"title":"Rapidly separable microneedle patches for controlled release of therapeutics for long-acting therapies","authors":"Chenyuan Wang , Xue Jiang , Yongnian Zeng , Richard N. Terry , Wei Li","doi":"10.1016/j.medidd.2021.100118","DOIUrl":"10.1016/j.medidd.2021.100118","url":null,"abstract":"<div><p>Microneedle (MN) patches have become an appealing approach for transdermal drug delivery due to their unique properties, such as enabling self-administration, causing no pain, increasing patient compliance, eliminating biohazardous sharps disposal and avoiding risk of needle-stick injury. Although dissolvable MN patches have achieved great success in bolus drug delivery in the skin, rapidly separable MN patches have recently attracted strong interest, especially in the treatment of chronic diseases, because of the short application time, long-acting efficacy and less frequent administration. In this review, we summarized three types of rapidly separable long-acting MN patches with different working mechanisms, followed by discussion of biomedical applications of those MN patches, including antigen delivery for vaccination, contraceptives delivery for long-term contraception, insulin delivery for diabetes treatment, ocular drug delivery for long-term therapy of ocular diseases, anti-tumor drug delivery for cancer therapy, pain relief drug delivery for analgesia, drug delivery for bacterial killing, and anti-obesity drug delivery for weight loss. Finally, we provided our perspectives on the future development of rapidly separable long-acting MN patches.</p></div>","PeriodicalId":33528,"journal":{"name":"Medicine in Drug Discovery","volume":"13 ","pages":"Article 100118"},"PeriodicalIF":0.0,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2590098621000397/pdfft?md5=c2c9a070139bf14f3d41de0d6e9f1494&pid=1-s2.0-S2590098621000397-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44453292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 13

Sustainability in drug discovery 药物发现的可持续性

Medicine in Drug Discovery Pub Date : 2021-12-01 DOI: 10.1016/j.medidd.2021.100107

Evelien Wynendaele , Christophe Furman , Bartosz Wielgomas , Per Larsson , Eelko Hak , Thomas Block , Serge Van Calenbergh , Nicolas Willand , Michal Markuszewski , Luke R. Odell , Gerrit J. Poelarends , Bart De Spiegeleer

引用次数: 4