Pub Date : 2024-10-29DOI: 10.1016/j.ejmech.2024.117008
Aichata Maiga , Maxwell Ampomah-Wireko , Hongteng Li , Zhengmin Fan , Ziwei Lin , Haojie Zhen , Stephen Kpekura , Chunli Wu
Many widely used conventional antibiotics have failed to show clinical efficacy against Pseudomonas aeruginosa (P. aeruginosa) due to the strain's rising resistance to most clinically relevant antimicrobials. P. aeruginosa uses quorum sensing to regulate its virulence and biofilm development, which contributes to its pathogenicity and drug resistance. This mechanism is responsible for the resurgence and persistence of infections. Therefore, targeting the virulence and pathogenicity of P. aeruginosa through quorum sensing (QS) is regarded as a potential target for anti-infective therapy. However, a number of natural and synthetic compounds have been demonstrated to interfere with quorum sensing, resulting in potential antibacterial agents. In this review, we discuss the mechanisms of P. aeruginosa QS and recent advances in the development of quorum sensing inhibitors (both synthetic and natural) that have the potential to become effective antibiotics.
{"title":"Multidrug-resistant bacteria quorum-sensing inhibitors: A particular focus on Pseudomonas aeruginosa","authors":"Aichata Maiga , Maxwell Ampomah-Wireko , Hongteng Li , Zhengmin Fan , Ziwei Lin , Haojie Zhen , Stephen Kpekura , Chunli Wu","doi":"10.1016/j.ejmech.2024.117008","DOIUrl":"10.1016/j.ejmech.2024.117008","url":null,"abstract":"<div><div>Many widely used conventional antibiotics have failed to show clinical efficacy against <em>Pseudomonas aeruginosa</em> (<em>P. aeruginosa</em>) due to the strain's rising resistance to most clinically relevant antimicrobials. <em>P. aeruginosa</em> uses quorum sensing to regulate its virulence and biofilm development, which contributes to its pathogenicity and drug resistance. This mechanism is responsible for the resurgence and persistence of infections. Therefore, targeting the virulence and pathogenicity of <em>P. aeruginosa</em> through quorum sensing (QS) is regarded as a potential target for anti-infective therapy. However, a number of natural and synthetic compounds have been demonstrated to interfere with quorum sensing, resulting in potential antibacterial agents. In this review, we discuss the mechanisms of <em>P. aeruginosa</em> QS and recent advances in the development of quorum sensing inhibitors (both synthetic and natural) that have the potential to become effective antibiotics.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117008"},"PeriodicalIF":6.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ejmech.2024.117011
Xinyan Qiu , Qianqian Gan , Tianxiong Ji , Hongchuang Xu , Kai Cui , Long Yi , Xing Yang , Min-Fu Yang
Fibroblast activation protein (FAP) has been an attractive target for cancer imaging and therapy. Radiolabeled FAP-targeting ligands have shown promising results for clinical applications. However, further improvements are ongoing in pursuit of increasing tumor uptake, prolonging tumor residence, and maintenance good tumor–to–background contrast for extensive theranostic application. Achieving a higher affinity of the precursor is one of the ways in research. In this study, we designed a series of FAP inhibitors based on N-(4-quinolinoyl)-Gly-2-cyanopyrrolidine and found compound QI-18 with an IC50 value of 0.50 nM, which is a 6.5-fold increase in potency over that of UAMC-1110 (IC50 of 3.25 nM). QI-18 was then functionalized with a DOTA chelator to obtain the ligand CY03 for further radiolabeling with 68Ga to obtain the radiotracer [68Ga]Ga-CY03. In BALB/c nude mice bearing U87MG tumor models, [68Ga]Ga-CY03 exhibited a high and specific uptake (10.30 ± 0.63 % ID/g at 1 h post-injection and 9.28 ± 1.60 % ID/g at 2 h post-injection), which represented 3.2- and 4.1-fold increases over those for [68Ga]Ga-FAPI-04 (3.24 ± 0.53 % ID/g and 2.25 ± 0.33 % ID/g, respectively). [68Ga]Ga-CY03 also showed higher tumor–to–blood and tumor–to–kidney ratios (7.62 ± 0.44 and 2.59 ± 0.27, respectively) than [68Ga]Ga-FAPI-04 (2.38 ± 0.47 and 0.98 ± 0.19, respectively). The results indicate that [68Ga]Ga-CY03 is a promising imaging agent to target FAP.
{"title":"Rational modifications on N-(4-quinolinoyl)-Gly-2-cyanopyrrolidine to develop fibroblast activation protein-targeted radioligands with improved affinity and tumor uptake","authors":"Xinyan Qiu , Qianqian Gan , Tianxiong Ji , Hongchuang Xu , Kai Cui , Long Yi , Xing Yang , Min-Fu Yang","doi":"10.1016/j.ejmech.2024.117011","DOIUrl":"10.1016/j.ejmech.2024.117011","url":null,"abstract":"<div><div>Fibroblast activation protein (FAP) has been an attractive target for cancer imaging and therapy. Radiolabeled FAP-targeting ligands have shown promising results for clinical applications. However, further improvements are ongoing in pursuit of increasing tumor uptake, prolonging tumor residence, and maintenance good tumor–to–background contrast for extensive theranostic application. Achieving a higher affinity of the precursor is one of the ways in research. In this study, we designed a series of FAP inhibitors based on <em>N</em>-(4-quinolinoyl)-Gly-2-cyanopyrrolidine and found compound <strong>QI-18</strong> with an IC<sub>50</sub> value of 0.50 nM, which is a 6.5-fold increase in potency over that of UAMC-1110 (IC<sub>50</sub> of 3.25 nM). <strong>QI-18</strong> was then functionalized with a DOTA chelator to obtain the ligand <strong>CY03</strong> for further radiolabeling with <sup>68</sup>Ga to obtain the radiotracer [<sup>68</sup>Ga]Ga-<strong>CY03</strong>. In BALB/c nude mice bearing U87MG tumor models, [<sup>68</sup>Ga]Ga-<strong>CY03</strong> exhibited a high and specific uptake (10.30 ± 0.63 % ID/g at 1 h post-injection and 9.28 ± 1.60 % ID/g at 2 h post-injection), which represented 3.2- and 4.1-fold increases over those for [<sup>68</sup>Ga]Ga-FAPI-04 (3.24 ± 0.53 % ID/g and 2.25 ± 0.33 % ID/g, respectively). [<sup>68</sup>Ga]Ga-<strong>CY03</strong> also showed higher tumor–to–blood and tumor–to–kidney ratios (7.62 ± 0.44 and 2.59 ± 0.27, respectively) than [<sup>68</sup>Ga]Ga-FAPI-04 (2.38 ± 0.47 and 0.98 ± 0.19, respectively). The results indicate that [<sup>68</sup>Ga]Ga-<strong>CY03</strong> is a promising imaging agent to target FAP.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117011"},"PeriodicalIF":6.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As a crucial regulator of oxidative homeostasis, seleno-protein glutathione peroxidase 4 (GPX4) represents the primary defense system against ferroptosis, making it a promising target with important clinical application prospects. From the discovery of covalent and allosteric sites in GPX4, substantial advancements in GPX4-targeted small molecules have been made through diverse discovery and design strategies in recent years. Moreover, as an emerging hotspot in drug development, seleno-organic compounds can functionally mimic GPX4 to reduce hydroperoxides. To facilitate the further development of selective ferroptosis mediators as potential pharmaceutical agents, this review comprehensively covers all GPX4-targeted small molecules, including inhibitors, degraders, and activators. In addition, seleno-organic compounds as GPX mimics are also included. We also provide perspectives regarding challenges and future research directions in this field.
{"title":"A prospective therapeutic strategy: GPX4-targeted ferroptosis mediators","authors":"Jia-Yu Qian, Chao-Yuan Lou, Yi-Li Chen, Lie-Feng Ma, Wei Hou, Zha-Jun Zhan","doi":"10.1016/j.ejmech.2024.117015","DOIUrl":"10.1016/j.ejmech.2024.117015","url":null,"abstract":"<div><div>As a crucial regulator of oxidative homeostasis, seleno-protein glutathione peroxidase 4 (GPX4) represents the primary defense system against ferroptosis, making it a promising target with important clinical application prospects. From the discovery of covalent and allosteric sites in GPX4, substantial advancements in GPX4-targeted small molecules have been made through diverse discovery and design strategies in recent years. Moreover, as an emerging hotspot in drug development, seleno-organic compounds can functionally mimic GPX4 to reduce hydroperoxides. To facilitate the further development of selective ferroptosis mediators as potential pharmaceutical agents, this review comprehensively covers all GPX4-targeted small molecules, including inhibitors, degraders, and activators. In addition, seleno-organic compounds as GPX mimics are also included. We also provide perspectives regarding challenges and future research directions in this field.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117015"},"PeriodicalIF":6.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ejmech.2024.117001
Wenjing Wang , Zhenzhuo Mo , Lu Han, Huijie Zuo, Yalu Chen, Yafei Fang, Xiang Li, Kai Wang, Jie Pan
Alzheimer's Disease (AD) is a neurodegenerative disease, of which β-amyloid (Aβ) deposition is one of the most important pathological features. It has been reported that during Aβ aggregation, the microenvironment around the Aβ protein is altered in terms of viscosity and polarity. In this work, we developed five novel hemicyanine fluorescent probes (MZs). After screening the photochemical properties, MZ-2 and 3 were found to enable the rapid detection of Aβ42 aggregates, which were also sensitive to ambient viscosity. After comparison the structure of probes, we also observed that extensions of conjugated π-systems effectively cause redshifts of excitation wavelength. In the meanwhile, hydroxyl groups with weaker ionization strengths are more responsive to Aβ42 aggregates than sulfonate groups, probably due to the small size of the hydroxyl group and the acidity. Overall, MZ-2 showed the best response to Aβ42 aggregates (15.35-fold) and viscosity (17.6-fold). MZ-2 can quickly cross the blood-brain barrier (BBB), enabling high-fidelity imaging of Aβ42 aggregates in the mice brain.
{"title":"A novel viscosity sensitive hemicyanine fluorescent dye for real-time imaging of amyloid-β aggregation","authors":"Wenjing Wang , Zhenzhuo Mo , Lu Han, Huijie Zuo, Yalu Chen, Yafei Fang, Xiang Li, Kai Wang, Jie Pan","doi":"10.1016/j.ejmech.2024.117001","DOIUrl":"10.1016/j.ejmech.2024.117001","url":null,"abstract":"<div><div>Alzheimer's Disease (AD) is a neurodegenerative disease, of which <em>β</em>-amyloid (A<em>β</em>) deposition is one of the most important pathological features. It has been reported that during A<em>β</em> aggregation, the microenvironment around the A<em>β</em> protein is altered in terms of viscosity and polarity. In this work, we developed five novel hemicyanine fluorescent probes (<strong>MZs</strong>). After screening the photochemical properties, <strong>MZ-2</strong> and <strong>3</strong> were found to enable the rapid detection of A<em>β</em><sub>42</sub> aggregates, which were also sensitive to ambient viscosity. After comparison the structure of probes, we also observed that extensions of conjugated π-systems effectively cause redshifts of excitation wavelength. In the meanwhile, hydroxyl groups with weaker ionization strengths are more responsive to A<em>β</em><sub>42</sub> aggregates than sulfonate groups, probably due to the small size of the hydroxyl group and the acidity. Overall, <strong>MZ-2</strong> showed the best response to A<em>β</em><sub>42</sub> aggregates (15.35-fold) and viscosity (17.6-fold). <strong>MZ-2</strong> can quickly cross the blood-brain barrier (BBB), enabling high-fidelity imaging of A<em>β</em><sub>42</sub> aggregates in the mice brain.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117001"},"PeriodicalIF":6.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ejmech.2024.117012
Sisi Chen , Ziling Zhi , Wing-Leung Wong , Wenchang Yuan , Ning Sun
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common multi-resistant organisms found in hospital-acquired infections and is associated with high morbidity and mortality. The development of new drugs and promising therapeutic strategies against MRSA is thus an urgent request. In recent years, some natural products have been demonstrated to show great potential in improving the efficacy of antibiotics to treat various drug-resistant bacteria, particularly MRSA. In this context, we aimed to analyze systematically from the prior arts that investigated the synergy between natural products and antibiotics against MRSA. These findings not only give us a better understanding on the mechanism of actions but also shed light on the bioactive molecular scaffolds identified from diverse natural products. In the present study, we concentratedly reviewed the studies that utilized natural products to enhance the potency of conventional antibiotics against MRSA in the last decade. The timely information reported herein may give meaningful insights into the molecular design of novel and potent antibacterial agents and/or effective therapeutics to combat MRSA for practical applications.
{"title":"Understanding the synergistic sensitization of natural products and antibiotics: An effective strategy to combat MRSA","authors":"Sisi Chen , Ziling Zhi , Wing-Leung Wong , Wenchang Yuan , Ning Sun","doi":"10.1016/j.ejmech.2024.117012","DOIUrl":"10.1016/j.ejmech.2024.117012","url":null,"abstract":"<div><div>Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) is one of the most common multi-resistant organisms found in hospital-acquired infections and is associated with high morbidity and mortality. The development of new drugs and promising therapeutic strategies against MRSA is thus an urgent request. In recent years, some natural products have been demonstrated to show great potential in improving the efficacy of antibiotics to treat various drug-resistant bacteria, particularly MRSA. In this context, we aimed to analyze systematically from the prior arts that investigated the synergy between natural products and antibiotics against MRSA. These findings not only give us a better understanding on the mechanism of actions but also shed light on the bioactive molecular scaffolds identified from diverse natural products. In the present study, we concentratedly reviewed the studies that utilized natural products to enhance the potency of conventional antibiotics against MRSA in the last decade. The timely information reported herein may give meaningful insights into the molecular design of novel and potent antibacterial agents and/or effective therapeutics to combat MRSA for practical applications.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117012"},"PeriodicalIF":6.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ejmech.2024.117003
Kuanrong Rong , Ziyun Li , Xiaoming Wu , Shan Gao , Jie Zhao , Jing Yang , Xiaorui Jiang , Jing Zhang , Wenjian Tang
FAAH inhibition can indirectly enhance endocannabinoid signaling to therapeutic levels, effectively preventing or slowing its progression of Alzheimer's disease (AD). Hence, the search for effective dual FAAH/cholinesterase inhibitors is considerable need for disease-modifying therapies. To this aim, we designed, synthesized, and tested three series of natural phenol carbamates. The majority of carbamates proved to be potent on a single target, amongst them, compound D12 containing paeonol motif was identified as an effective dual BuChE/FAAH inhibitor, with well-balanced nanomolar activity (IC50 = 81 and 400 nM for hBuChE and hFFAH, respectively). D12 possessed BBB penetrating ability, benign safety, neuroprotection and pseudo-irreversible BuChE inhibition (Kd = 2.11 μM, k2 = 2.27 min−1), showing good drug-like properties. D12 also modulated the BV2 microglial polarization to inhibit neuroinflammation. In vivo study verified that D12 improved Aβ1-41-induced learning impairments in AD mouse model for both short- and long-term memory responses. Thus, the dual activity of D12 could lead to a potentially more effective treatment for the counteraction of AD progression.
{"title":"Natural phenol carbamates: Selective BuChE/FAAH dual inhibitors show neuroprotection in an Alzheimer's disease mouse model","authors":"Kuanrong Rong , Ziyun Li , Xiaoming Wu , Shan Gao , Jie Zhao , Jing Yang , Xiaorui Jiang , Jing Zhang , Wenjian Tang","doi":"10.1016/j.ejmech.2024.117003","DOIUrl":"10.1016/j.ejmech.2024.117003","url":null,"abstract":"<div><div>FAAH inhibition can indirectly enhance endocannabinoid signaling to therapeutic levels, effectively preventing or slowing its progression of Alzheimer's disease (AD). Hence, the search for effective dual FAAH/cholinesterase inhibitors is considerable need for disease-modifying therapies. To this aim, we designed, synthesized, and tested three series of natural phenol carbamates. The majority of carbamates proved to be potent on a single target, amongst them, compound <strong>D12</strong> containing paeonol motif was identified as an effective dual BuChE/FAAH inhibitor, with well-balanced nanomolar activity (IC<sub>50</sub> = 81 and 400 nM for <em>h</em>BuChE and <em>h</em>FFAH, respectively). <strong>D12</strong> possessed BBB penetrating ability, benign safety, neuroprotection and pseudo-irreversible BuChE inhibition (<em>K</em><sub>d</sub> = 2.11 μM, <em>k</em><sub>2</sub> = 2.27 min<sup>−1</sup>), showing good drug-like properties. <strong>D12</strong> also modulated the BV2 microglial polarization to inhibit neuroinflammation. <em>In vivo</em> study verified that <strong>D12</strong> improved A<em>β</em><sub>1-41</sub>-induced learning impairments in AD mouse model for both short- and long-term memory responses. Thus, the dual activity of <strong>D12</strong> could lead to a potentially more effective treatment for the counteraction of AD progression.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117003"},"PeriodicalIF":6.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ejmech.2024.117006
Yaolei Li , Jing Fan , Hongyu Jin , Feng Wei , Shuangcheng Ma
The quality control of Traditional Chinese Medicine (TCM) is crucial for ensuring its efficacy and safety. Traditional methods, however, have limitations in fully capturing the natural essence of TCM, thus hindering the comprehensive exhibition of its authenticity. Addressing this challenge requires the establishment of a scientific and reasonable quality control system, which poses significant complexities due to the TCM unique attributes. Our research team conducted in-depth exploration of the elemental fingerprints of TCM, amassing a robust theoretical and practical foundation. In this review, we presented a comprehensive review of the core value, advanced technologies, and classic cases of elemental fingerprints. We introduced a novel perspective that integrated inorganic and organic components, overcoming traditional paradigms. The review analysis highlighted unique role of elemental fingerprints in revealing the scientific connotation of TCM. Furthermore, we proposed an innovative strategy for identifying key components, which effectively addressed the limitations of traditional methods and elevated the overall evaluation standards for TCM. This strategy was supported by emerging technologies such as artificial intelligence, metallomics, and hyperspectral imaging. Looking ahead, the application prospects of the combined strategy of elemental fingerprints and key components were promising. It not only provided a solid foundation for the formulation of TCM quality control strategies but also introduced new methodologies and tools to the field of regulatory science and scientific oversight of TCM.
{"title":"New vision for TCM quality control: Elemental fingerprints and key ingredient combination strategy for identification and evaluation of TCMs","authors":"Yaolei Li , Jing Fan , Hongyu Jin , Feng Wei , Shuangcheng Ma","doi":"10.1016/j.ejmech.2024.117006","DOIUrl":"10.1016/j.ejmech.2024.117006","url":null,"abstract":"<div><div>The quality control of Traditional Chinese Medicine (TCM) is crucial for ensuring its efficacy and safety. Traditional methods, however, have limitations in fully capturing the natural essence of TCM, thus hindering the comprehensive exhibition of its authenticity. Addressing this challenge requires the establishment of a scientific and reasonable quality control system, which poses significant complexities due to the TCM unique attributes. Our research team conducted in-depth exploration of the elemental fingerprints of TCM, amassing a robust theoretical and practical foundation. In this review, we presented a comprehensive review of the core value, advanced technologies, and classic cases of elemental fingerprints. We introduced a novel perspective that integrated inorganic and organic components, overcoming traditional paradigms. The review analysis highlighted unique role of elemental fingerprints in revealing the scientific connotation of TCM. Furthermore, we proposed an innovative strategy for identifying key components, which effectively addressed the limitations of traditional methods and elevated the overall evaluation standards for TCM. This strategy was supported by emerging technologies such as artificial intelligence, metallomics, and hyperspectral imaging. Looking ahead, the application prospects of the combined strategy of elemental fingerprints and key components were promising. It not only provided a solid foundation for the formulation of TCM quality control strategies but also introduced new methodologies and tools to the field of regulatory science and scientific oversight of TCM.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117006"},"PeriodicalIF":6.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ejmech.2024.117010
Lai Wei , Peng Yu , Haomeng Wang , Jiang Liu
Adeno-associated viruses (AAVs) are leading platforms for in vivo delivery of gene therapies, with six licensed AAV-based therapeutics attributed to their non-pathogenic nature, low immunogenicity, and high efficiency. In the realm of gene-based vaccines, one of the most vital therapeutic areas, AAVs are also emerging as promising delivery tools. We scrutinized AAVs, focusing on their virological properties, as well as bioengineering and chemical modifications to demonstrate their significant potential in gene vaccine delivery, and detailing the preparation of AAV particles. Additionally, we summarized the use of AAV vectors in vaccines for both infectious and non-infectious diseases, such as influenza, COVID-19, Alzheimer's disease, and cancer. Furthermore, this review, along with the latest clinical trial updates, provides a comprehensive overview of studies on the potential of using AAV vectors for gene vaccine delivery. It aims to deepen our understanding of the challenges and limitations in nucleic acid delivery and pave the way for future clinical success.
{"title":"Adeno-associated viral vectors deliver gene vaccines","authors":"Lai Wei , Peng Yu , Haomeng Wang , Jiang Liu","doi":"10.1016/j.ejmech.2024.117010","DOIUrl":"10.1016/j.ejmech.2024.117010","url":null,"abstract":"<div><div>Adeno-associated viruses (AAVs) are leading platforms for <em>in vivo</em> delivery of gene therapies, with six licensed AAV-based therapeutics attributed to their non-pathogenic nature, low immunogenicity, and high efficiency. In the realm of gene-based vaccines, one of the most vital therapeutic areas, AAVs are also emerging as promising delivery tools. We scrutinized AAVs, focusing on their virological properties, as well as bioengineering and chemical modifications to demonstrate their significant potential in gene vaccine delivery, and detailing the preparation of AAV particles. Additionally, we summarized the use of AAV vectors in vaccines for both infectious and non-infectious diseases, such as influenza, COVID-19, Alzheimer's disease, and cancer. Furthermore, this review, along with the latest clinical trial updates, provides a comprehensive overview of studies on the potential of using AAV vectors for gene vaccine delivery. It aims to deepen our understanding of the challenges and limitations in nucleic acid delivery and pave the way for future clinical success.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117010"},"PeriodicalIF":6.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ejmech.2024.117004
Samuel Desta Guma , Zhaoyin Zhou , Kang Song , Feipu Yang , Jin Suo , Yan Zhang , Emmanuel Mintah Bonku , Abdullajon Odilov , Guanghui Tian , Zhijian Xu , Xiangrui Jiang , Qiumeng Zhang , Weiliang Zhu , Jingshan Shen
Given the high pathogenicity and rapid mutation rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to sustain efforts in drug research and development. Herein, we present the design, synthesis, and evaluation of peptidomimetic spiropyrrolidine derivatives as potent 3CLpro inhibitors against SARS-CoV-2. Among the synthesized derivatives, several compounds exhibited high potency in inhibiting 3CLpro, with IC50 values ranging from 21 nM to 53 nM. Notably, compounds 9b and 9h displayed improved enzymatic inhibition (IC50 = 25 nM and 21 nM, respectively) compared to nirmatrelvir (47 nM). Compound 9b showed enhanced stability in human and mouse liver microsomes compared to nirmatrelvir, whereas 9h exhibited similar stability to nirmatrelvir in both species. Furthermore, compound 9h displayed exceptional potency in cellular assays targeting the SARS-CoV-2 replicon within Huh7 cells, with a single-digit nanomolar activity that is 5.6 times better than that of nirmatrelvir. In a pharmacokinetic study in mice (PO, 20 mg/kg), compound 9h exhibited a prolonged plasma half-life (T1/2 = 2.58 h) compared to nirmatrelvir (T1/2 = 0.51 h) and demonstrated an AUC(0-t) value (1106 h∗ng/mL) equivalent to that of nirmatrelvir (1023 h∗ng/mL). These findings indicate that compound 9h is a promising lead for developing a novel 3CLpro inhibitor against SARS-CoV-2.
{"title":"Discovery of peptidomimetic spiropyrrolidine derivatives as novel 3CLpro inhibitors against SARS-CoV -2","authors":"Samuel Desta Guma , Zhaoyin Zhou , Kang Song , Feipu Yang , Jin Suo , Yan Zhang , Emmanuel Mintah Bonku , Abdullajon Odilov , Guanghui Tian , Zhijian Xu , Xiangrui Jiang , Qiumeng Zhang , Weiliang Zhu , Jingshan Shen","doi":"10.1016/j.ejmech.2024.117004","DOIUrl":"10.1016/j.ejmech.2024.117004","url":null,"abstract":"<div><div>Given the high pathogenicity and rapid mutation rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is imperative to sustain efforts in drug research and development. Herein, we present the design, synthesis, and evaluation of peptidomimetic spiropyrrolidine derivatives as potent 3CL<sup>pro</sup> inhibitors against SARS-CoV-2. Among the synthesized derivatives, several compounds exhibited high potency in inhibiting 3CL<sup>pro</sup>, with IC<sub>50</sub> values ranging from 21 nM to 53 nM. Notably, compounds <strong>9b</strong> and <strong>9h</strong> displayed improved enzymatic inhibition (IC<sub>50</sub> = 25 nM and 21 nM, respectively) compared to nirmatrelvir (47 nM). Compound <strong>9b</strong> showed enhanced stability in human and mouse liver microsomes compared to nirmatrelvir, whereas <strong>9h</strong> exhibited similar stability to nirmatrelvir in both species. Furthermore, compound <strong>9h</strong> displayed exceptional potency in cellular assays targeting the SARS-CoV-2 replicon within Huh7 cells, with a single-digit nanomolar activity that is 5.6 times better than that of nirmatrelvir. In a pharmacokinetic study in mice (PO, 20 mg/kg), compound <strong>9h</strong> exhibited a prolonged plasma half-life (T<sub>1/2</sub> = 2.58 h) compared to nirmatrelvir (T<sub>1/2</sub> = 0.51 h) and demonstrated an AUC<sub>(0-t)</sub> value (1106 h∗ng/mL) equivalent to that of nirmatrelvir (1023 h∗ng/mL). These findings indicate that compound <strong>9h</strong> is a promising lead for developing a novel 3CL<sup>pro</sup> inhibitor against SARS-CoV-2.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117004"},"PeriodicalIF":6.0,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1016/j.ejmech.2024.117002
Tobias Winge, Dirk Schepmann, Judith Schmidt, Bernhard Wünsch
The σ1 receptor plays a key role in the regulation of various processes in the human body; it is involved in the development of neurodegenerative and neuropsychiatric diseases and is overexpressed in several human tumors rendering it an important target for potential drug candidates. In this project, spirocyclic σ1 receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ1 receptor affinity and selectivity over related targets. The σ1 affinity of the ligands was correlated with their lipophilicity (logD7.4 value) giving insight into their lipophilic ligand efficiency (LLE). The (pyridin-3-yl)methyl derivative 5i showed a promising balance of high σ1 affinity (Ki(σ1) = 3.9 nM) and selectivity (>250-fold) as well as high LLE of 5.8. 5i has a high plasma protein binding (89 %) and promising metabolic stability in the presence of mouse liver microsomes and NADPH (83 % intact after 90 min). Increasing the size of the piperidine ring of the spirocyclic ligands 5 to an azepane ring led to considerably increased σ1 affinity (Ki(5a) = 1.2 nM, Ki(23a) = 0.42 nM) and selectivity over σ2 receptors (5a: 45-fold, 23a: 150-fold).
{"title":"Synthesis and structure-affinity relationships of spirocyclic σ1 receptor ligands with tetrahydropyran scaffold","authors":"Tobias Winge, Dirk Schepmann, Judith Schmidt, Bernhard Wünsch","doi":"10.1016/j.ejmech.2024.117002","DOIUrl":"10.1016/j.ejmech.2024.117002","url":null,"abstract":"<div><div>The σ<sub>1</sub> receptor plays a key role in the regulation of various processes in the human body; it is involved in the development of neurodegenerative and neuropsychiatric diseases and is overexpressed in several human tumors rendering it an important target for potential drug candidates. In this project, spirocyclic σ<sub>1</sub> receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ<sub>1</sub> receptor affinity and selectivity over related targets. The σ<sub>1</sub> affinity of the ligands was correlated with their lipophilicity (log<em>D</em><sub>7.4</sub> value) giving insight into their lipophilic ligand efficiency (LLE). The (pyridin-3-yl)methyl derivative <strong>5i</strong> showed a promising balance of high σ<sub>1</sub> affinity (<em>K</em><sub>i</sub>(σ<sub>1</sub>) = 3.9 nM) and selectivity (>250-fold) as well as high LLE of 5.8. <strong>5i</strong> has a high plasma protein binding (89 %) and promising metabolic stability in the presence of mouse liver microsomes and NADPH (83 % intact after 90 min). Increasing the size of the piperidine ring of the spirocyclic ligands <strong>5</strong> to an azepane ring led to considerably increased σ<sub>1</sub> affinity (<em>K</em><sub>i</sub>(<strong>5a</strong>) = 1.2 nM, <em>K</em><sub>i</sub>(<strong>23a</strong>) = 0.42 nM) and selectivity over σ<sub>2</sub> receptors (<strong>5a</strong>: 45-fold, <strong>23a</strong>: 150-fold).</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117002"},"PeriodicalIF":6.0,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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