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Dual PPAR delta/gamma agonist offer therapeutic potential for Alzheimer's disease

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Neural Regeneration Research 2024年第6期19卷 1175-1176页

作者： Ian Steinke Meenakshi Singh Rajesh Amin Department of drug discovery and Development Auburn University

The increasing incidence of Alzheimer’s disease(AD) in the aging population, indicates the critical need for the development of novel targeted molecular therapies for ameliorating AD pathology. Moreover, clinical and preclinical evidence demonstrates that peroxisomal proliferator activating receptors(PPAR) agonists regulate energy and lipid homeostasis in models of diabetes, as well as improve spatial memory in animal models of AD(Khan et al., 2019).

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Recent advances in the culture-independent discovery of natural products using metagenomic approaches

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Chinese Journal of Natural Medicines 2024年第2期22卷 100-111页

作者： SHEN Yiping LIU Nan WANG Zongqiang Laboratory of Microbial drug discovery China Pharmaceutical UniversityNanjing 211198China

Natural products derived from bacterial sources have long been pivotal in the discovery of drug leads.However,the cultivation of only about 1%of bacteria in laboratory settings has left a significant portion of biosynthetic diversity hidden within the genomes of uncultured bacteria.Advances in sequencing technologies now enable the exploration of genetic material from these metagenomes through culture-independent methods.This approach involves extracting genetic sequences from environmental DNA and applying a hybrid methodology that combines functional screening,sequence tag-based homology screening,and bioinformatic-assisted chemical synthesis.Through this process,numerous valuable natural products have been identified and synthesized from previously uncharted metagenomic territories.This paper provides an overview of the recent advancements in the utilization of culture-independent techniques for the discovery of novel biosynthetic gene clusters and bioactive small molecules within metagenomic libraries.

关键词： Metagenomics Culture-independent approach Natural product Functional screening Sequence tag-based homology screening Syn-BNP

Nuance of inward rectifying potassium(Kir) channel dysfunctions in neurodegenerative diseases

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Neural Regeneration Research 2024年第6期19卷 1195-1196页

作者： Benjamin Garland Linlin Ma Griffith Institute for drug discovery & School of Environment and Science Griffith University

Neurodegenerative disorders are highly prevalent and diverse in nature. Their manifestation largely depends on the cell types involved, with aberrant inflammatory episodes progressively inducing a constellation of phenotypes that are classified into specific diseases based on their neuropathological traits. The two most prevalent neurodegenerative diseases worldwide,

关键词： K-ATP CHANNELS PARKINSONS-DISEASE MODEL

AI enhances drug discovery and development

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National Science Review 2024年第3期11卷 52-54页

作者： Fang Bai Shiliang Li Honglin Li Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech University Lingang Laboratory Innovation center for AI and drug discovery East China Normal University

The advent of the third wave of artificial intelligence(AI) heralds a new era in drug discovery. AI-powered techniques can be characteristic of identifying features that are difficult for humans to interpret from big ...

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Click chemistry and natural products

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Chinese Journal of Natural Medicines 2024年第2期22卷 97-99页

作者： ZHANG Chen WU Jianbing ZHANG Yihua HUANG Zhangjian State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic DiseasesCenter of Drug DiscoveryChina Pharmaceutical UniversityNanjing 210009China State Key Laboratory of Pathogenesis Prevention and Treatment of High Incidence Diseases in Central AsiaXinjiang Key Laboratory of Natural Medicines Active Components and Drug Release TechnologySchool of PharmacyXinjiang Medical UniversityUrumqi 830054China

The 2022 Nobel Prize in Chemistry was awarded to American scientists Carolyn Bertozzi,K.Barry Sharpless,and Danish scientist Morten P.Merdahl for their contributions to the development of click chemistry and bioorthog... 详细信息

关键词： Click chemistry Natural product Target identification drug discovery

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

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Acta Pharmaceutica Sinica B 2024年第2期14卷 517-532页

作者： Shuang Xiang Xiaoyun Lu International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative drug discovery of Chinese Ministry of Education(MOE) Guangdong Provincial Key Laboratory of New Drug Design and EvaluationGuangzhou City Key Laboratory of Precision Chemical Drug DevelopmentSchool of PharmacyJinan UniversityGuangzhou 510632China

Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these fusions.Currently,two generations TRK inhibitors have been developed.The representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations.However,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical need.In this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mutations mediated resistance.Additionally,we concluded our perspectives on new challenges and future directions in this field.

关键词： NTRK fusions TRK kinase Clinical resistance xDFG mutations Selective type II inhibitors

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Sigmatropic rearrangements of B(MIDA)-propargylic alcohols towards the diverse synthesis of α-functionalized organoborons

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Science China Chemistry 2024年第2期67卷 568-575页

作者： Jiasheng Qian Li-Cai Liu Zhi-Hao Chen Yuan Liu Yin Li Qingjiang Li Honggen Wang Guangdong Key Laboratory of Chiral Molecule and drug discovery School of Pharmaceutical SciencesSun Yat-Sen UniversityGuangzhou510006China

α-Functionalized organoborons are useful building blocks and key structural elements in functional molecules.Their previous synthesis relied on the famous Matteson reaction or the late-stage borylative modification of alkynes or alkenes.Recently,the synthetic transformation of borylated building blocks offers another useful strategy and is currently actively explored.We report herein that B(MIDA)-propargylic alcohols(BPAs) are a useful type of borylated building blocks.Bearing two complementary functional group handles(alkyne and hydroxyl) in close proximity,the redox-neutral [3,3] and [2,3] sigmatropic rearrangements of BPAs allow the efficient synthesis of several types of α-functionalized boronates,including α,β-unsaturated acylborons,α-S/P-substituted allenylborons,boryl-substituted thiazoles and a borylated α,β-unsaturated hydrazine,some of which are otherwise challenging targets using other synthetic methods.

关键词： organoboron diverse synthesis sigmatropic rearrangement heteroarene amide

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Combination of AAV-delivered tumor suppressor PTEN with anti-PD-1 loaded depot gel for enhanced antitumor immunity

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Acta Pharmaceutica Sinica B 2024年第1期14卷 350-364页

作者： Yongshun Zhang Lan Yang Yangsen Ou Rui Hu Guangsheng Du Shuang Luo Fuhua Wu Hairui Wang Zhiqiang Xie Yu Zhang Chunting He Cheng Ma Tao Gong Ling Zhang Zhirong Zhang Xun Sun Key Laboratory of drug-Targeting and drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China Med-X center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Recent clinical studies have shown that mutation of phosphatase and tensin homolog deleted on chromosome 10(PTEN)gene in cancer cells may be associated with immunosuppressive tumor microenvironment(TME)and poor response to immune checkpoint blockade(ICB)therapy.Therefore,efficiently restoring PTEN gene expression in cancer cells is critical to improving the responding rate to ICB therapy.Here,we screened an adeno-associated virus(AAV)capsid for efficient PTEN gene delivery into B16F10 tumor cells.We demonstrated that intratumorally injected AAV6-PTEN successfully restored the tumor cell PTEN gene expression and effectively inhibited tumor progression by inducing tumor cell immunogenic cell death(ICD)and increasing immune cell infiltration.Moreover,we developed an anti-PD-1 loaded phospholipid-based phase separation gel(PPSG),which formed an in situ depot and sustainably release anti-PD-1 drugs within 42 days in vivo.In order to effectively inhibit the recurrence of melanoma,we further applied a triple therapy based on AAV6-PTEN,PPSG^(@anti-PD-1)and CpG,and showed that this triple therapy strategy enhanced the synergistic antitumor immune effect and also induced robust immune memory,which completely rejected tumor recurrence.We anticipate that this triple therapy could be used as a new tumor combination therapy with stronger immune activation capacity and tumor inhibition efficacy.

关键词： Triple therapy Adeno-associated virus PTEN PPSG@anti-PD-1 CpG Immunogenic cell death Antitumor immune response Immune memory

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Regulatory role of peroxynitrite in advanced glycation end products mediated diabetic cardiovascular complications

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World Journal of Diabetes 2024年第3期15卷 572-574页

作者： Asis Bala Pharmacology and drug discovery Research Laboratory Division of Life SciencesInstitute of Advanced Study in Science and TechnologyGuwahati 781035AssamIndia

The Advanced Glycation End Products(AGE)binding with its receptor can increase reactive oxygen species(ROS)generation through specific signaling mediators.The effect of superoxide(O2-)and O2-mediated ROS and reactive nitrogen species depends on their concentration and location of formation.Nitric oxide(NO)has anti-inflammatory and anticoagulant properties and a vasodilation effect,but NO can be deactivated by reacting with O_(2)^(-).This reaction between NO and O2-produces the potent oxidant ONOO−.Therefore,ONOO-'s regulatory role in AGEs in diabetic cardiovascular complications must considered as a regulator of cardiovascular complications in diabetes.

关键词： Diabetes Cardiovascular complication Advanced glycation end products Reactive oxygen species Reactive nitrogen species Peroxynitrite