Article
Pharmacology & Pharmacy
Pawel K. Halik, Przemyslaw Kozminski, Joanna Matalinska, Piotr F. J. Lipinski, Aleksandra Misicka, Ewa Gniazdowska
Summary: Currently, there is a search for promising radiopharmaceuticals that target NK1R-positive tumors based on the structure of small molecular antagonists of the neurokinin-1 receptor. In this study, three novel aprepitant derivatives were synthesized and labeled with Ga-68 and Lu-177. The evaluated radioconjugates showed increased lipophilicity and stability, and demonstrated higher affinity and better binding capacity to the human NK1 receptor compared to the reference Substance P derivative used in glioblastoma therapy.
Review
Biochemistry & Molecular Biology
Rafael Covenas, Francisco D. Rodriguez, Prema Robinson, Miguel Munoz
Summary: The substance P/neurokinin-1 receptor system plays a role in cancer progression, and Aprepitant, as a broad-spectrum anticancer drug, can inhibit tumor cell proliferation and migration, enhance the effectiveness of radiotherapy or chemotherapy, and improve the quality of life for patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Prema Robinson, Rafael Covenas, Miguel Munoz
Summary: Background: Chemotherapy has limitations in cancer treatment due to its ineffectiveness and severe side effects. The substance P/neurokinin-1 receptor (NK-1R) system has been identified as a potential target for cancer treatment. Aprepitant combined with major chemotherapeutic agents has shown the potential to enhance antitumor activity and reduce side effects. Objective: This review aims to provide an update on combination therapy studies involving chemotherapy/radiotherapy and NK-1R antagonist in cancer treatment. Conclusion: This combination strategy may revolutionize chemotherapy and radiotherapy by improving antitumor activity and reducing side effects, leading to higher cure rates and better quality of life for cancer patients.
CURRENT MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Eugenia M. Clerico, Alexandra K. Pozhidaeva, Rachel M. Jansen, Can Ozden, Joseph M. Tilitsky, Lila M. Gierasch
Summary: This research investigated how Hsp70 binds to full-length client proteins by analyzing complex structures and experiments, revealing that many sequences can choose from multiple binding modes and binding preference depends on the compatibility of substrate residue side chains with binding pockets. The study also found that multiple chaperones can simultaneously bind to multiple sites on the protein substrate, and these sites behave independently.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Malihe Golestaneh, Mohsen Firoozrai, Hossein Javid, Seyed Isaac Hashemy
Summary: SW480 colorectal cancer cells exhibited significant metastatic activity following incubation with increasing doses of SP, as evidenced by increased MMP-2/MMP-9 enzyme activity, gene overexpression, and enhanced cell migration. Treatment with AP significantly reduced all SP-mediated metastatic effects (p-Value < 0.001).
MOLECULAR BIOLOGY REPORTS
(2022)
Article
Reproductive Biology
Somayeh Kouhetsani, Homayoun Khazali, Hassan Rajabi-Maham
Summary: This study aimed to clarify the effects of orexin and Substance-P (SP) neuropeptide receptor antagonists on ovarian steroidogenesis in a rat model of polycystic ovary syndrome (PCOS). The results showed that the antagonists reduced Cyp19a1 gene expression and increased testosterone levels, suggesting their potential role in modulating abnormal ovarian steroidogenesis in PCOS.
JOURNAL OF OVARIAN RESEARCH
(2023)
Article
Multidisciplinary Sciences
Mahmoud S. Ahmed, Ping Wang, Ngoc Uyen Nhi Nguyen, Yuji Nakada, Ivan Menendez-Montes, Muhammad Ismail, Robert Bachoo, Mark Henkemeyer, Hesham A. Sadek, Enas S. Kandil
Summary: Previous studies showed that tetracycline antibiotics demeclocycline, chlortetracycline, and minocycline can inhibit EphB1 kinase activity, which was further confirmed in vivo by inhibiting phosphorylation of EphB1 in mice and effectively blocking neuropathic pain. This suggests that these drugs could be repurposed for treating neuropathic pain and potentially other conditions that benefit from inhibition of EphB1 receptor kinase activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Abhimanyu K. Singh, Sergio E. Martinez, Weijie Gu, Hoai Nguyen, Dominique Schols, Piet Herdewijn, Steven De Jonghe, Kalyan Das
Summary: The authors discovered a transient P-pocket created by HIV reverse transcriptase while sliding over a DNA substrate and developed a cryo-EM platform for lead optimization. By screening 300 drug-like fragments, they identified two leads that bind to the P-pocket, which is resilient to drug-resistance mutations and composed of structural elements from polymerase active site, primer grip, and template-primer. An engineered RT/DNA aptamer complex was utilized to trap the transient P-pocket and structures of the RT/DNA complex in the presence of an inhibitory fragment were determined.
NATURE COMMUNICATIONS
(2021)
Article
Medicine, Research & Experimental
Cagri Becerik, Cigdem T. Karaca, Zuhal Ozcan, Selim Kul, Sema Z. Toros
Summary: This study investigates the allergic changes in the larynx caused by allergic rhinitis and compares the effects of aprepitant with antihistamines and LTRAs on nasal symptoms and histopathological changes in the nasal and laryngeal mucosa. The results show that antihistamines and LTRAs significantly reduce nasal itching and sneezing symptoms, while aprepitant does not affect nasal symptoms. Aprepitant significantly reduces pseudostratification in the larynx.
Article
Engineering, Environmental
Yu Yang, Shujing Cheng, Yingyu Zheng, Ting Xue, Jian-Wen Huang, Lilan Zhang, Yunyun Yang, Rey-Ting Guo, Chun -Chi Chen
Summary: Poly(butylene adipate-co-terephthalate) (PBAT) is a widely used synthetic polyester in the packaging and agricultural industries. Its accumulation as waste poses a burden to ecosystems, but the use of renewable enzymes for PBAT decomposition offers an eco-friendly solution. Cutinase has been shown to be the most effective PBAT-degrading enzyme, and an engineered cutinase called TfCut-DM can completely decompose PBAT film to terephthalate (TPA). This study reports the crystal structures of a variant of leaf compost cutinase in complex with soluble fragments of PBAT and identifies a distal TPA-binding site that shows higher diversity among cutinases. Modification of this site in TfCut-DM leads to variants with higher activity, resulting in faster degradation of PBAT film to TPA.
JOURNAL OF HAZARDOUS MATERIALS
(2024)
Review
Biochemistry & Molecular Biology
Zoe Li, Jie Liu, Fan Dong, Nancy Chang, Ruili Huang, Menghang Xia, Tucker A. Patterson, Huixiao Hong
Summary: The United States is facing a severe opioid crisis, with increasing numbers of deaths caused by both prescription and illegal opioids over the past two decades. Opioids are important for pain treatment but also highly addictive, making it difficult to combat this public health issue.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Sourav Pal, Barnali Paul, Purbita Bandopadhyay, Nagothy Preethy, Dipika Sarkar, Oindrila Rahaman, Sunny Goon, Swarnali Roy, Dipyaman Ganguly, Arindam Talukdar
Summary: The study provides a rational design approach through molecular docking analysis and MD simulations to facilitate the development of novel small molecule hTLR7 antagonists based on different chemical scaffolds.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Mariia Radaeva, Huifang Li, Eric LeBlanc, Kush Dalal, Fuqiang Ban, Fabrice Ciesielski, Bonny Chow, Helene Morin, Shannon Awrey, Kriti Singh, Paul S. Rennie, Nada Lallous, Artem Cherkasov
Summary: The mutation-driven transformation of anti-androgen drugs into receptor agonists poses a challenge for prostate cancer treatment. We developed inhibitors targeting the receptor's DNA-binding domain and identified a few that exhibited partial agonistic effects towards mutated forms of the receptor. By studying the molecular basis, we designed derivatives to eliminate cross-reactivity with the receptor's androgen binding site while maintaining anti-DNA-binding domain potency.
Article
Biochemistry & Molecular Biology
Rebecca L. Frkic, Jordan L. Pederick, Aimee J. Horsfall, Blagojce Jovcevski, Elise E. Crame, Wioleta Kowalczyk, Tara L. Pukala, Mi Ra Chang, Jie Zheng, Anne-Laure Blayo, Andrew D. Abell, Theodore M. Kamenecka, Joshua S. Harbort, Jeffrey R. Harmer, Patrick R. Griffin, John B. Bruning
Summary: Inverse agonists of PPAR gamma, such as SR10221, exhibit reduced side effects and impressive insulin-sensitizing properties. This study reveals the molecular mechanism by which SR10221 interacts with the ligand binding domain of PPAR gamma, showing a novel binding mode in the presence of a corepressor peptide. The findings provide direct evidence for corepressor-driven ligand conformation and have implications for the development of safer and more effective insulin sensitizers.
ACS CHEMICAL BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Ruiqi Liu, Tianyi Yuan, Ranran Wang, Difei Gong, Shoubao Wang, Guanhua Du, Lianhua Fang
Summary: This paper reviews the regulation of endothelin receptors and their pathways in normal physiological processes and disease processes, and describes the mechanistic roles of ET receptor antagonists that are currently approved and used in clinical studies. Current clinical researches on ET are focused on the development of multi-target combinations and novel delivery methods to improve efficacy and patient compliance while reducing side effects. Future research directions and trends of ET targets, including monotherapy and precision medicine, are also described in this review.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Haoyi Ge, Huixia Wang, Benxun Pan, Dandan Feng, Canyong Guo, Lingyun Yang, Dongsheng Liu, Kurt Wuethrich
Summary: GPCRs are a membrane protein family present in higher organisms, including humans, and play a key role in cellular responses and physiological functions. Understanding the structure and dynamics of GPCRs is crucial for drug design and involves the modulation of extrinsic ligands and intracellular binding partners.
Article
Multidisciplinary Sciences
Benxun Pan, Dongsheng Liu, Lingyun Yang, Kurt Wuthrich
Summary: Comparisons of G protein-coupled receptor (GPCR) complexes with agonists and antagonists reveal differences in the width of the orthosteric ligand binding groove. F-19-NMR experiments with the neurokinin 1 receptor (NK1R) show transient structure fluctuations with amplitudes up to at least 6 angstrom. The data suggest extensive promiscuity of initial ligand binding and large-scale floating motions of GPCR transmembrane helices in the lipid bilayer.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Editorial Material
Cell Biology
Jens Lund, Christoffer Clemmensen, Thue W. Schwartz
Summary: In this recent study, Li et al. propose that Lac-Phe, a metabolite derived from lactate released during high-intensity exercise, acts as an exercise hormone that suppresses appetite and obesity.
Article
Endocrinology & Metabolism
Ahmed M. Abdelmoez, Oksana Dmytriyeva, Yasemin-Xiomara Zurke, Mette Trauelsen, Alesandra A. Marica, Mladen Savikj, Jonathon A. B. Smith, Claudia Monaco, Thue W. Schwartz, Anna Krook, Nicolas J. Pillon
Summary: Succinate released by skeletal muscle activates SUCNR1/GPR91, but it is unclear which cell types respond to succinate and the directionality of communication. This study found that SUCNR1 is expressed in macrophages but not in muscle cells, suggesting that the adaptive response of skeletal muscle to exercise is mediated via paracrine mechanisms involving macrophages.
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
(2023)
Article
Cardiac & Cardiovascular Systems
Maria J. Forteza, Martin Berg, Andreas Edsfeldt, Jangming Sun, Roland Baumgartner, Ilona Kareinen, Felipe Beccaria Casagrande, Ulf Hedin, Song Zhang, Ivan Vuckovic, Petras P. Dzeja, Konstantinos A. Polyzos, Anton Gistera, Mette Trauelsen, Thue W. Schwartz, Lea Dib, Joerg Herrmann, Claudia Monaco, Ljubica Matic, Isabel Goncalves, Daniel F. J. Ketelhuth
Summary: Recent studies have shown a link between cellular metabolism and the chronic inflammatory process of atherosclerosis. The PDK/PDH axis has been identified as a major metabolic pathway regulating vascular inflammation and atherogenesis, and targeting it with DCA could be a promising treatment for atherosclerosis.
CARDIOVASCULAR RESEARCH
(2023)
Article
Gastroenterology & Hepatology
Iain R. Tough, Mari L. Lund, Bhavik A. Patel, Thue W. Schwartz, Helen M. Cox
Summary: This study investigates the efficacy of 5-HT signaling and its interaction with incretin hormones in different regions of the mouse intestine. The results show that 5-HT has the highest levels in the ascending colon mucosa and acts through both 5-HT3 and 5-HT4 receptors. Additionally, GLP-1 and GIP have interactions with 5-HT and affect the colonic mucosa.
NEUROGASTROENTEROLOGY AND MOTILITY
(2023)
Article
Multidisciplinary Sciences
Dimitra M. Lappa, Abraham S. Meijnikman, Kimberly A. Krautkramer, Lisa M. Olsson, Omrum Aydin, Anne-Sophie Van Rijswijk, Yair I. Z. E. Acherman, Maurits De Brauw, Valentina A. Tremaroli, Louise E. Olofsson, Annika Lundqvist, Siv A. K. Hjorth, Boyang W. Ji, Victor E. A. Gerdes, Albert K. Groen, Thue W. Schwartz, Max Nieuwdorp, Fredrik Baeckhed, Jens Nielsen
Summary: Weight loss through bariatric surgery is effective in treating or preventing obesity related diseases, but the long-term weight loss response varies among patients. This study conducted multiple omics analyses on individuals undergoing bariatric surgery to identify metabolic differences and explore their relationship with weight loss response. Five distinct metabotypes were identified based on plasma metabolome analysis, showing differential enrichment in pathways related to immune functions, fatty acid metabolism, protein signaling, and obesity pathogenesis. The gut metagenome of the heavily medicated metabotypes was significantly enriched in Prevotella and Lactobacillus species. Each metabotype responded differently to bariatric surgery in terms of weight loss after 12 months. This study provides a path for patient stratification and improved clinical treatments.
Article
Endocrinology & Metabolism
Jacob Emil Petersen, Maria Hauge Pedersen, Oksana Dmytriyeva, Emilie Nellemose, Tulika Arora, Maja Storm Engelstoft, Wesley B. Asher, Jonathan A. Javitch, Thue W. Schwartz, Mette Trauelsen
Summary: The activation of FFAR1 can induce both IP3/Ca2+ signaling pathway and cAMP signaling pathway, and the co-activation of these two pathways is required for the highly efficient hormone secretion induced by second-generation FFAR1 agonists. Adcy2 gene is highly expressed in enteroendocrine cells of the intestine and may mediate Gq-driven cAMP signaling response.
MOLECULAR METABOLISM
(2023)
Article
Multidisciplinary Sciences
Huixia Wang, Wanhui Hu, Tiandan Xu, Ya Yuan, Dongsheng Liu, Kurt Wuthrich
Summary: Crystal and cryo-EM structures of GLP-1R and GCGR bound with their peptide ligands were obtained, confirming the importance of the ECD in ligand binding. Paramagnetic NMR relaxation enhancement measurements revealed GLP-1 selectively interacts with the extracellular surface of GLP-1R. The study also showed cross-reactivity between GLP-1R and GCGR with glucagon and GLP-1, respectively, which has implications for medical treatments.
Letter
Medicine, Research & Experimental
Yanliu Fan, Xi Lin, Benxun Pan, Bo Chen, Dongsheng Liu, Kurt Wuethrich, Fei Xu
Article
Biochemistry & Molecular Biology
Canyong Guo, Lingyun Yang, Zhijun Liu, Dongsheng Liu, Kurt Wuthrich
Summary: Eight hundred and twenty-six human G protein-coupled receptors (GPCRs) play a significant role in mediating the actions of hormones, neurotransmitters, and drugs. Studying the structure and dynamics of GPCRs in lipid bilayer environments is crucial for understanding their functionality and developing new drugs. This study incorporates the A(2A) adenosine receptor into lipid nanodiscs, providing a detergent-free environment for structural studies using NMR. The findings demonstrate the stability and mimicry of the lipid nanodisc and LMNG/CHS micelles in preserving the overall fold and local structure of the receptor.
Article
Biochemistry & Molecular Biology
Samuel A. Bradley, Beata J. Lehka, Frederik G. Hansson, Khem B. Adhikari, Daniela Rago, Paulina Rubaszka, Ahmad K. Haidar, Ling Chen, Lea G. Hansen, Olga Gudich, Konstantina Giannakou, Bettina Lengger, Ryan T. Gill, Yoko Nakamura, Thomas Duge de Bernonville, Konstantinos Koudounas, David Romero-Suarez, Ling Ding, Yijun Qiao, Thomas M. Frimurer, Anja A. Petersen, Sebastien Besseau, Sandeep Kumar, Nicolas Gautron, Celine Melin, Jillian Marc, Remi Jeanneau, Sarah E. O'Connor, Vincent Courdavault, Jay D. Keasling, Jie Zhang, Michael K. Jensen
Summary: This study reports a yeast platform for the de novo biosynthesis of medicinal plant compounds. Using refactored plant pathways, the researchers successfully synthesized 19 halogenated derivatives with therapeutic potential.
NATURE CHEMICAL BIOLOGY
(2023)
Letter
Pharmacology & Pharmacy
Jinmiao Lu, Hao Liu, Qingtong Zhou, Ming-Wei Wang, Zhiping Li
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Cell Biology
Ping Luo, Wenbo Feng, Shanshan Ma, Antao Dai, Kai Wu, Xianyue Chen, Qingning Yuan, Xiaoqing Cai, Dehua Yang, Ming-Wei Wang, H. Eric Xu, Yi Jiang
Summary: G protein-coupled receptors (GPCRs) are regulated by accessory proteins such as melanocortin receptor accessory protein 1 (MRAP1), which plays a crucial role in the regulation of melanocortin receptor 2 (MC2R). The activation of MC2R by adrenocorticotropic hormone (ACTH) and its involvement in glucocorticoid biogenesis have significant effects on the hypothalamic-pituitary-adrenal axis and related disorders. This study presents the cryo-electron microscopy structure of the ACTH-bound MC2R-G(s)-MRAP1 complex, revealing the unique structure and stabilizing effect of MRAP1 on ACTH binding and MC2R activation. The findings provide insights into GPCR regulation and the design of therapeutic agents targeting MC2R.
Article
Oncology
Kathrine Lundo, Oksana Dmytriyeva, Louise Spohr, Eliana Goncalves-Alves, Jiayi Yao, Laia P. Blasco, Mette Trauelsen, Muthulakshmi Ponniah, Marc Severin, Albin Sandelin, Marie Kveiborg, Thue W. Schwartz, Stine F. Pedersen
Summary: This study reveals the mechanism of lactate receptor GPR81 in breast cancer, which promotes tumor invasiveness by downregulating the Notch pathway ligand DLL4. This finding is of great significance for the treatment of breast cancer.