查看更多>>摘要：Solute carriers(SLCs)constitute the largest superfamily of membrane transporter proteins.These transporters,present in various SLC families,play a vital role in energy metabolism by facilitating the transport of diverse substances,including glucose,fatty acids,amino acids,nucleotides,and ions.They actively participate in the regulation of glucose metabolism at various steps,such as glucose uptake(e.g.,SLC2A4/GLUT4),glucose reabsorption(e.g.,SLC5A2/SGLT2),thermogenesis(e.g.,SLC25A7/UCP-1),and ATP production(e.g.,SLC25A4/ANT1 and SLC25A5/ANT2).The activities of these trans-porters contribute to the pathogenesis of type 2 diabetes mellitus(T2DM).Notably,SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption,leading to groundbreaking advancements in diabetes drug discovery.Alongside SLC5A2,multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy.SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms,such as rosiglitazone(SLCO1B1/OATP1B1)and metformin(SLC22A1-3/OCT1-3 and SLC47A1,2/MATE1,2).By consoli-dating insights into the biological activities and clinical relevance of SLC transporters in T2DM,this re-view offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.
查看更多>>摘要：According to the World Health Organization's world report on hearing,nearly 2.5 billion people worldwide will suffer from hearing loss by 2050,which may contribute to a severe impact on in-dividual life quality and national economies.Sensorineural hearing loss(SNHL)occurs commonly as a result of noise exposure,aging,and ototoxic drugs,and is pathologically characterized by the impairment of mechanosensory hair cells of the inner ear,which is mainly triggered by reactive oxygen species accu-mulation,inflammation,and mitochondrial dysfunction.Though recent advances have been made in un-derstanding the ability of cochlear repair and regeneration,there are still no effective therapeutic drugs for SNHL.Chinese herbal medicine which is widely distributed and easily accessible in China has demon-strated a unique curative effect against SNHL with higher safety and lower cost compared with Western medicine.Herein we present trends in research for Chinese herbal medicine for the treatment of SNHL,and elucidate their molecular mechanisms of action,to pave the way for further research and development of novel effective drugs in this field.
查看更多>>摘要：G protein-coupled receptors(GPCRs)are a large family of membrane protein receptors,and Takeda G protein-coupled receptor 5(TGR5)is a member of this family.As a membrane receptor,TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism,including the processes of energy consumption,weight loss and blood glucose homeostasis.Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver,obesity and diabetes.With the global obesity situation becoming more and more serious,a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed.In this review,we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target,and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor bind-ing sites and ligands,which can effectively provide new ideas for ligand research and promote drug research.
查看更多>>摘要：DNA-encoded chemical library(DEL)links the power of amplifiable genetics and the non-self-replicating chemical phenotypes,generating a diverse chemical world.In analogy with the biological world,the DEL world can evolve by using a chemical central dogma,wherein DNA replicates using the PCR reactions to amplify the genetic codes,DNA sequencing transcripts the genetic information,and DNA-compatible synthesis translates into chemical phenotypes.Importantly,DNA-compatible synthesis is the key to expanding the DEL chemical space.Besides,the evolution-driven selection system pushes the chemicals to evolve under the selective pressure,i.e.,desired selection strategies.In this perspective,we summarized recent advances in expanding DEL synthetic toolbox and panning strategies,which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.
查看更多>>摘要：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 in-hibitors have been developed.The representative second-generation inhibitors selitrectinib and repotrec-tinib 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 seli-trectinib 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 mu-tations mediated resistance.Additionally,we concluded our perspectives on new challenges and future directions in this field.
查看更多>>摘要：Epigenetic pathways play a critical role in the initiation,progression,and metastasis of can-cer.Over the past few decades,significant progress has been made in the development of targeted epige-netic modulators(e.g.,inhibitors).However,epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy,toxicities,lack of subtype selectivity,and drug resistance.As a result,the design of new epigenetic modulators(e.g.,degraders)such as PROTACs,molecular glue,and hydro-phobic tagging(HyT)degraders has garnered significant attention from both academia and pharmaceu-tical industry,and numerous epigenetic degraders have been discovered in the past decade.In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023)targeting epigenetic proteins for cancer therapy,focusing on the rational design,pharmacodynamics,pharmacokinetics,clin-ical status,and crystal structure information of these degraders.Importantly,we also provide deep in-sights into the potential challenges and corresponding remedies of this approach to drug design and development.Overall,we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.
查看更多>>摘要：Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery,as demon-strated by the approval of patisiran for amyloidosis therapy in 2018.To illuminate the unique superiority of lipid nanovehicles in RNA delivery,in this review,we first introduce various RNA therapeutics,describe systemic delivery barriers,and explain the lipid components and methods used for lipid nanovehicle prep-aration.Then,we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to sys-temic RNA delivery.Finally,the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed.Our objective is to provide a comprehensive over-view showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery,inspiring the development of more high-performance RNA lipid nanovesicles in the future.
查看更多>>摘要：Calcium-based biomaterials have been intensively studied in the field of drug delivery owing to their excellent biocompatibility and biodegradability.Calcium-based materials can also deliver contrast agents,which can enhance real-time imaging and exert a Ca2+-interfering therapeutic effect.Based on these characteristics,amorphous calcium carbonate(ACC),as a brunch of calcium-based biomaterials,has the potential to become a widely used biomaterial.Highly functional ACC can be either discovered in natural organisms or obtained by chemical synthesis However,the standalone presence of ACC is un-stable in vivo.Additives are required to be used as stabilizers or core-shell structures formed by perme-able layers or lipids with modified molecules constructed to maintain the stability of ACC until the ACC carrier reaches its destination.ACC has high chemical instability and can produce biocompatible products when exposed to an acidic condition in vivo,such as Ca2+with an immune-regulating ability and CO2 with an imaging-enhancing ability.Owing to these characteristics,ACC has been studied for self-sacrificing templates of carrier construction,targeted delivery of oncology drugs,immunomodulation,tu-mor imaging,tissue engineering,and calcium supplementation.Emphasis in this paper has been placed on the origin,structural features,and multiple applications of ACC.Meanwhile,ACC faces many chal-lenges in clinical translation,and long-term basic research is required to overcome these challenges.We hope that this study will contribute to future innovative research on ACC.
查看更多>>摘要：Aldehyde oxidase(AOX)is a molybdoenzyme that is primarily expressed in the liver and is involved in the metabolism of drugs and other xenobiotics.AOX-mediated metabolism can result in un-expected outcomes,such as the production of toxic metabolites and high metabolic clearance,which can lead to the clinical failure of novel therapeutic agents.Computational models can assist medicinal chem-ists in rapidly evaluating the AOX metabolic risk of compounds during the early phases of drug discovery and provide valuable clues for manipulating AOX-mediated metabolism liability.In this study,we devel-oped a novel graph neural network called AOMP for predicting AOX-mediated metabolism.AOMP in-tegrated the tasks of metabolic substrate/non-substrate classification and metabolic site prediction,while utilizing transfer learning from 13C nuclear magnetic resonance data to enhance its performance on both tasks.AOMP significantly outperformed the benchmark methods in both cross-validation and external testing.Using AOMP,we systematically assessed the AOX-mediated metabolism of common fragments in kinase inhibitors and successfully identified four new scaffolds with AOX metabolism liability,which were validated through in vitro experiments.Furthermore,for the convenience of the community,we established the first online service for AOX metabolism prediction based on AOMP,which is freely avail-able at https://aomp.alphama.com.cn.
查看更多>>摘要：Alzheimer's disease(AD)is a leading cause of dementia in the elderly.Mitogen-activated protein kinase phosphatase 1(MKP-1)plays a neuroprotective role in AD.However,the molecular mech-anisms underlying the effects of MKP-1 on AD have not been extensively studied.MicroRNAs(miR-NAs)regulate gene expression at the post-transcriptional level,thereby repressing mRNA translation.Here,we reported that the microRNA-429-3p(miR-429-3p)was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells.We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region(3'UTR).Inhibition of miR-429-3p by its antagomir(A-miR-429)restored the expression of MKP-1 to a control level and conse-quently reduced the amyloidogenic processing of APP and Aβ accumulation.More importantly,intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potenti-ation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated ki-nase(ERKl/2)-mediated GluA1 hyperphosphorylation at Ser831 site,thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors(AMPARs).Together,these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice,suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.
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