Pharmacology & Therapeutics最新文献

Exploring the landscape of post-translational modification in drug discovery. 探索药物发现中翻译后修饰的全貌。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-16 DOI: 10.1016/j.pharmthera.2024.108749

Yuhao Cao, Tianyi Yu, Ziang Zhu, Yuanjiao Zhang, Shanliang Sun, Nianguang Li, Chunyan Gu, Ye Yang

{"title":"Exploring the landscape of post-translational modification in drug discovery.","authors":"Yuhao Cao, Tianyi Yu, Ziang Zhu, Yuanjiao Zhang, Shanliang Sun, Nianguang Li, Chunyan Gu, Ye Yang","doi":"10.1016/j.pharmthera.2024.108749","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2024.108749","url":null,"abstract":"<p><p>Post-translational modifications (PTMs) play a crucial role in regulating protein function, and their dysregulation is frequently associated with various diseases. The emergence of epigenetic drugs targeting factors such as histone deacetylases (HDACs) and histone methyltransferase enhancers of zeste homolog 2 (EZH2) has led to a significant shift towards precision medicine, offering new possibilities to overcome the limitations of traditional therapeutics. In this review, we aim to systematically explore how small molecules modulate PTMs. We discuss the direct targeting of enzymes involved in PTM pathways, the modulation of substrate proteins, and the disruption of protein-enzyme interactions that govern PTM processes. Additionally, we delve into the emerging strategy of employing multifunctional molecules to precisely regulate the modification levels of proteins of interest (POIs). Furthermore, we examine the specific characteristics of these molecules, evaluating their therapeutic benefits and potential drawbacks. The goal of this review is to provide a comprehensive understanding of PTM-targeting strategies and their potential for personalized medicine, offering a forward-looking perspective on the evolution of precision therapeutics.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108749"},"PeriodicalIF":12.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New drug discovery and development from natural products: Advances and strategies. 从天然产品中发现和开发新药物：进展与战略。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-16 DOI: 10.1016/j.pharmthera.2024.108752

Yixin Wang, Fan Wang, Wenxiu Liu, Yifei Geng, Yahong Shi, Yu Tian, Bin Zhang, Yun Luo, Xiaobo Sun

{"title":"New drug discovery and development from natural products: Advances and strategies.","authors":"Yixin Wang, Fan Wang, Wenxiu Liu, Yifei Geng, Yahong Shi, Yu Tian, Bin Zhang, Yun Luo, Xiaobo Sun","doi":"10.1016/j.pharmthera.2024.108752","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2024.108752","url":null,"abstract":"<p><p>Natural products (NPs) have a long history as sources for drug discovery, more than half of approved drugs are related to NPs, which also exhibit multifaceted advantages in the clinical treatment of complex diseases. However, bioactivity screening of NPs, target identification, and design optimization require continuously improved strategies, the complexity of drug mechanism of action and the limitations of technological strategies pose numerous challenges to the development of new drugs. This review begins with an overview of bioactivity- and target-based drug development patterns for NPs, advances in NP screening and derivatization, and the advantages and problems of major targets such as genes and proteins. Then, target-based drugs as well as identification and validation methods are further discussed to elucidate their mechanism of action. Subsequently, the current status and development trend of the application of traditional and emerging technologies in drug discovery and development of NPs are systematically described. Finally, the collaborative strategy of multi-technology integration and multi-disciplinary intersection is emphasized for the challenges faced in the identification, optimization, activity evaluation, and clinical application of NPs. It is hoped to provide a systematic overview and inspiration for exploring new drugs from natural resources in the future.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108752"},"PeriodicalIF":12.0,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neurobiology of cancer: Adrenergic signaling and drug repurposing 癌症神经生物学：肾上腺素能信号转导与药物再利用。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-10 DOI: 10.1016/j.pharmthera.2024.108750

Zi-Kai Dong , Yong-Fei Wang , Wei-Ping Li , Wei-Lin Jin

引用次数: 0

The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products 抗击神经退行性疾病的潜在治疗策略：关注天然产品。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-09 DOI: 10.1016/j.pharmthera.2024.108751

Li Gao , Xi-Na Yang , Yi-Xiao Dong , Yi-Jia Han , Xin-Yue Zhang , Xin-Le Zhou , Ying Liu , Fang Liu , Jian-Song Fang , Jian-Long Ji , Zheng-Run Gao , Xue-Mei Qin

{"title":"The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products","authors":"Li Gao , Xi-Na Yang , Yi-Xiao Dong , Yi-Jia Han , Xin-Yue Zhang , Xin-Le Zhou , Ying Liu , Fang Liu , Jian-Song Fang , Jian-Long Ji , Zheng-Run Gao , Xue-Mei Qin","doi":"10.1016/j.pharmthera.2024.108751","DOIUrl":"10.1016/j.pharmthera.2024.108751","url":null,"abstract":"<div><div>Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), Huntington disease (HD), and Multiple sclerosis (MS), pose a significant global health challenge due to their intricate pathology and limited therapeutic interventions. Natural products represent invaluable reservoirs for combating these neurodegenerative diseases by targeting key pathological hallmarks such as protein aggregation, synaptic dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, inflammation, and neuronal cell death. This review provides an in-depth analysis of the mechanisms and therapeutic targets of natural products for their neuroprotective effects. Furthermore, it elucidates the current progress of clinical trials investigating the potential of natural products in delaying neurodegeneration. The objective of this review is to enhance the comprehension of natural products in the prevention and treatment of neurodegenerative diseases, offering new insights and potential avenues for future pharmaceutical research.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108751"},"PeriodicalIF":12.0,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease 丁酰胆碱酯酶和 p38α 丝裂原活化蛋白激酶的双重抑制：治疗阿尔茨海默病的新方法。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-07 DOI: 10.1016/j.pharmthera.2024.108748

Svit Ferjančič Benetik, Damijan Knez, Aleš Obreza, Urban Košak, Stanislav Gobec

{"title":"Dual inhibition of butyrylcholinesterase and p38α mitogen-activated protein kinase: A new approach for the treatment of Alzheimer's disease","authors":"Svit Ferjančič Benetik, Damijan Knez, Aleš Obreza, Urban Košak, Stanislav Gobec","doi":"10.1016/j.pharmthera.2024.108748","DOIUrl":"10.1016/j.pharmthera.2024.108748","url":null,"abstract":"<div><div>The simultaneous targeting of neuroinflammation and cholinergic hypofunction, the key pathological changes in Alzheimer's disease (AD), is not addressed by drugs currently in clinical trials, highlighting a critical therapeutic gap. We propose that dual-acting small molecules that inhibit butyrylcholinesterase (BChE) and mitogen-activated protein kinase p38α (p38α MAPK) represent a novel strategy to combat AD. This hypothesis is supported by cellular and animal studies as well as <em>in silico</em> modelling showing that it is possible to act simultaneously on both enzymes. Amyloid beta (Aβ) plaques trigger a pro-inflammatory microglial response that overactivates p38α MAPK, leading to increased Aβ synthesis, tau hyperphosphorylation, and altered synaptic plasticity. Overactivated microglia exacerbate neuroinflammation and cholinergic degeneration, ultimately leading to cognitive impairment. Structural similarities between the binding sites of BChE and p38α MAPK provide a promising basis for the development of dual inhibitors that could alleviate AD symptoms and address the underlying pathology.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108748"},"PeriodicalIF":12.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacological modulation of respiratory control: Ampakines as a therapeutic strategy. 呼吸控制的药理调节：安非他酮作为一种治疗策略。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-07 DOI: 10.1016/j.pharmthera.2024.108744

Sabhya Rana, Anna F Fusco, Jeffrey M Witkin, Daniel P Radin, Rok Cerne, Arnold Lippa, David D Fuller

{"title":"Pharmacological modulation of respiratory control: Ampakines as a therapeutic strategy.","authors":"Sabhya Rana, Anna F Fusco, Jeffrey M Witkin, Daniel P Radin, Rok Cerne, Arnold Lippa, David D Fuller","doi":"10.1016/j.pharmthera.2024.108744","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2024.108744","url":null,"abstract":"<p><p>Ampakines are a class of compounds that are positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and enhance glutamatergic neurotransmission. Glutamatergic synaptic transmission and AMPA receptor activation are fundamentally important to the genesis and propagation of the neural impulses driving breathing, including respiratory motoneuron depolarization. Ampakines therefore have the potential to modulate the neural control of breathing. In this paper, we describe the influence of ampakines on respiratory motor output in health and disease. We dissect the molecular mechanisms underlying ampakine action, delineate the diverse targets of ampakines along the respiratory neuraxis, survey the spectrum of respiratory disorders in which ampakines have been tested, and culminate with an examination of how ampakines modulate respiratory function after spinal cord injury. Collectively, the studies reviewed here indicate that ampakines may be a useful adjunctive strategy to pair with conventional respiratory rehabilitation approaches in conditions with impaired neural activation of the respiratory muscles.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"108744"},"PeriodicalIF":12.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lessons learned from 20 years of preclinical testing in pediatric cancers 从 20 年的儿科癌症临床前试验中汲取的经验教训。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-05 DOI: 10.1016/j.pharmthera.2024.108742

Malcolm A. Smith , Peter J. Houghton , Richard B. Lock , John M. Maris , Richard Gorlick , Raushan T. Kurmasheva , Xiao-Nan Li , Beverly A. Teicher , Jeffrey H. Chuang , Filemon S. Dela Cruz , Michael A. Dyer , Andrew L. Kung , Michael W. Lloyd , Yael P. Mossé , Timothy M. Stearns , Elizabeth A. Stewart , Carol J. Bult , Stephen W. Erickson

{"title":"Lessons learned from 20 years of preclinical testing in pediatric cancers","authors":"Malcolm A. Smith , Peter J. Houghton , Richard B. Lock , John M. Maris , Richard Gorlick , Raushan T. Kurmasheva , Xiao-Nan Li , Beverly A. Teicher , Jeffrey H. Chuang , Filemon S. Dela Cruz , Michael A. Dyer , Andrew L. Kung , Michael W. Lloyd , Yael P. Mossé , Timothy M. Stearns , Elizabeth A. Stewart , Carol J. Bult , Stephen W. Erickson","doi":"10.1016/j.pharmthera.2024.108742","DOIUrl":"10.1016/j.pharmthera.2024.108742","url":null,"abstract":"<div><div>Programs for preclinical testing of targeted cancer agents in murine models of childhood cancers have been supported by the National Cancer Institute (NCI) since 2004. These programs were established to work collaboratively with industry partners to address the paucity of targeted agents for pediatric cancers compared with the large number of agents developed and approved for malignancies primarily affecting adults. The distinctive biology of pediatric cancers and the relatively small numbers of pediatric cancer patients are major challenges for pediatric oncology drug development. These factors are exacerbated by the division of cancers into multiple subtypes that are further sub-classified by their genomic properties. The imbalance between the large number of candidate agents and small patient populations requires careful prioritization of agents developed for adult cancers for clinical evaluation in children with cancer. The NCI-supported preclinical pediatric programs have published positive and negative results of efficacy testing for over 100 agents to aid the pediatric research community in identifying the most promising candidates to move forward for clinical testing in pediatric oncology. Here, we review and summarize lessons learned from two decades of experience with the design and execution of preclinical trials of antineoplastic agents in murine models of childhood cancers.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108742"},"PeriodicalIF":12.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Nutraceuticals target androgen receptor-splice variants (AR-SV) to manage castration resistant prostate cancer (CRPC) 营养保健品以雄激素受体拼接变体（AR-SV）为靶点，用于治疗对阉割有抵抗力的前列腺癌（CRPC）。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-02 DOI: 10.1016/j.pharmthera.2024.108743

Ashish Tyagi , Balaji Chandrasekaran , Vaibhav Shukla , Neha Tyagi , Arun K. Sharma , Chendil Damodaran

{"title":"Nutraceuticals target androgen receptor-splice variants (AR-SV) to manage castration resistant prostate cancer (CRPC)","authors":"Ashish Tyagi , Balaji Chandrasekaran , Vaibhav Shukla , Neha Tyagi , Arun K. Sharma , Chendil Damodaran","doi":"10.1016/j.pharmthera.2024.108743","DOIUrl":"10.1016/j.pharmthera.2024.108743","url":null,"abstract":"<div><div>Every year, prostate cancer is diagnosed in millions of men. The androgen receptor's (AR) unchecked activation is crucial in causing the development and progression of prostate cancer. Second-generation anti-androgen therapies, which primarily focus on targeting the Ligand Binding Domain (LBD) of AR, are effective for most patients. However, the adverse effects pose significant challenges in managing the disease. Furthermore, genetic mutations or the emergence of AR splice variants create an even more complex tumor environment, fostering resistance to these treatments. Natural compounds and their analogs, while showing a lower toxicity profile and a potential for selective AR splice variants inhibition, are constrained by their bioavailability and therapeutic efficacy. Nonetheless, recent breakthroughs in using natural derivatives to target AR and its splice variants have shown promise in treating chemoresistant castration-resistant prostate cancer (CRPC). This review will discuss the role of AR variants, particularly androgen receptor splice variant 7 (AR-V7), in CRPC and investigate the latest findings on how natural compounds and their derivatives target AR and AR splice variants.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108743"},"PeriodicalIF":12.0,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lipoprotection in cardiovascular diseases 心血管疾病中的血脂保护。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-02 DOI: 10.1016/j.pharmthera.2024.108747

Marcel Benkhoff , Amin Polzin

引用次数: 0

The voltage sensitivity of G-protein coupled receptors: Unraveling molecular mechanisms and physiological implications G 蛋白偶联受体的电压敏感性：揭示分子机制和生理意义。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2024-11-01 DOI: 10.1016/j.pharmthera.2024.108741

Marin Boutonnet , Moritz Bünemann , Julie Perroy

{"title":"The voltage sensitivity of G-protein coupled receptors: Unraveling molecular mechanisms and physiological implications","authors":"Marin Boutonnet , Moritz Bünemann , Julie Perroy","doi":"10.1016/j.pharmthera.2024.108741","DOIUrl":"10.1016/j.pharmthera.2024.108741","url":null,"abstract":"<div><div>In the landscape of proteins controlled by membrane voltage (V<sub>m</sub>), like voltage-gated ionotropic channels, the emergence of the voltage sensitivity within the vast family of G-protein coupled receptors (GPCRs) marked a significant milestone at the onset of the 21st century. Since its discovery, extensive research has been devoted to understanding the intricate relationship between V<sub>m</sub> and GPCRs. Approximately 30 GPCRs out of a family comprising more than 800 receptors have been implicated in V<sub>m</sub>-dependent positive and negative regulation. GPCRs stand out as the quintessential regulators of synaptic transmission in neurons, where they encounter substantial variations in V<sub>m</sub>. However, the molecular mechanism underlying the V<sub>m</sub> sensor of GPCRs remains enigmatic, hindered by the scarcity of mutant GPCRs insensitive to V<sub>m</sub> yet functionally intact, impeding a comprehensive understanding of this unique property in physiology. Nevertheless, two decades of dedicated research have furnished numerous insights into the molecular aspects of GPCR V<sub>m</sub>-sensing, accompanied by recently proposed physiological roles as well as pharmacological potential, which we encapsulate in this review. The V<sub>m</sub> sensitivity of GPCRs emerges as a pivotal attribute, shedding light on previously unforeseen roles in synaptic transmission and extending beyond, underscoring its significance in cellular signaling and physiological processes.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"264 ","pages":"Article 108741"},"PeriodicalIF":12.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0