查看更多>>摘要：T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens,thereby engaging with CD3 on the T cell receptor.This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells.These anti-bodies have emerged as one of the most promising avenues within tumor immunotherapy.However,despite success in treating hematological malignancies,significant advancements in solid tumors have yet to be explored.In this review,we aim to address the critical challenges associated with T cell-redirecting bispecific antibodies and explore novel strategies to overcome these obstacles,with the ulti-mate goal of expanding the application of this therapy to include solid tumors.
查看更多>>摘要：For over two decades,the development of B-cell lymphoma-2(Bcl-2)family therapeutics has primarily focused on anti-apoptotic proteins,resulting in the first-in-class drugs called BH3 mimetics,especially for Bcl-2 inhibitor Venetoclax.The pro-apoptotic protein Bcl-2-associated X protein(BAX)plays a crucial role as the executioner protein of the mitochondrial regulated cell death,contributing to organismal development,tissue homeostasis,and immunity.The dysregulation of BAX is closely asso-ciated with the onset and progression of diseases characterized by pathologic cell survival or death,such as cancer,neurodegeneration,and heart failure.In addition to conducting thorough investigations into the physiological modulation of BAX,research on the regulatory mechanisms of small molecules identified through biochemical screening approaches has prompted the identification of functional and potentially druggable binding sites on BAX,as well as diverse all-molecule BAX modulators.This review presents recent advancements in elucidating the physiological and pharmacological modulation of BAX and in identifying potentially druggable binding sites on BAX.Furthermore,it highlights the structural and mechanistic insights into small-molecule modulators targeting diverse binding surfaces or conformations of BAX,offering a promising avenue for developing next-generation apoptosis modulators to treat a wide range of diseases associated with dysregulated cell death by directly targeting BAX.
查看更多>>摘要：Targeted protein degradation(TPD)represented by proteolysis targeting chimeras(PROTACs)marks a significant stride in drug discovery.A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond degradation.Non-small-molecule-based approaches play an irreplaceable role in this field.A wide variety of agents spanning a broad chemical spectrum,including peptides,nucleic acids,antibodies,and even vaccines,which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing paradigms.Herein we summa-rize the burgeoning non-small molecule technological platforms inspired by PROTACs,including three major trajectories,to provide insights for the design strategies based on novel paradigms.
查看更多>>摘要：The visualization of drugs in living systems has become key techniques in modem therapeu-tics.Recent advancements in optical imaging technologies and molecular design strategies have revolu-tionized drug visualization.At the subcellular level,super-resolution microscopy has allowed exploration of the molecular landscape within individual cells and the cellular response to drugs.Moving beyond sub-cellular imaging,researchers have integrated multiple modes,like optical near-infrared Ⅱ imaging,to study the complex spatiotemporal interactions between drugs and their surroundings.By combining these visualization approaches,researchers gain supplementary information on physiological parameters,meta-bolic activity,and tissue composition,leading to a comprehensive understanding of drug behavior.This review focuses on cutting-edge technologies in drug visualization,particularly fluorescence imaging,and the main types of fluorescent molecules used.Additionally,we discuss current challenges and prospects in targeted drug research,emphasizing the importance of multidisciplinary cooperation in advancing drug visualization.With the integration of advanced imaging technology and molecular design,drug visuali-zation has the potential to redefine our understanding of pharmacology,enabling the analysis of drug micro-dynamics in subcellular environments from new perspectives and deepening pharmacological research to the levels of the cell and organelles.
查看更多>>摘要：The clinical efficacy of current cancer therapies falls short,and there is a pressing demand to integrate new targets with conventional therapies.Autophagy,a highly conserved self-degradation pro-cess,has received considerable attention as an emerging therapeutic target for cancer.With the rapid development of nanomedicine,nanomaterials have been widely utilized in cancer therapy due to their unrivaled delivery performance.Hence,considering the potential benefits of integrating autophagy and nanotechnology in cancer therapy,we outline the latest advances in autophagy-based nanotherapeutics.Based on a brief background related to autophagy and nanotherapeutics and their impact on tumor pro-gression,the feasibility of autophagy-based nanotherapeutics for cancer treatment is demonstrated.Further,emerging nanotherapeutics developed to modulate autophagy are reviewed from the perspective of cell signaling pathways,including modulation of the mammalian target of rapamycin(mTOR)pathway,autophagy-related(ATG)and its complex expression,reactive oxygen species(ROS)and mito-phagy,interference with autophagosome-lysosome fusion,and inhibition of hypoxia-mediated autophagy.In addition,combination therapies in which nano-autophagy modulation is combined with chemotherapy,phototherapy,and immunotherapy are also described.Finally,the prospects and challenges of autophagy-based nanotherapeutics for efficient cancer treatment are envisioned.
Ahmed O.ElzoghbyOmar SamirHagar E.EmamAhmed Soliman...
2475-2504页
查看更多>>摘要：Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment(TME)leading to failure of immune response.Numerous therapeutic strategies including chemotherapy,radiotherapy,photodynamic,photothermal,magnetic,chemodynamic,sonodynamic and oncolytic therapy,have been developed to induce immuno-genic cell death(ICD)of cancer cells and thereby elicit immunogenicity and boost the antitumor immune response.However,many challenges hamper the clinical application of ICD inducers resulting in modest immunogenic response.Here,we outline the current state of using nanomedicines for boosting ICD of cancer cells.Moreover,synergistic approaches used in combination with ICD inducing nanomedicines for remodeling the TME via targeting immune checkpoints,phagocytosis,macrophage polarization,tu-mor hypoxia,autophagy and stromal modulation to enhance immunogenicity of dying cancer cells were analyzed.We further highlight the emerging trends of using nanomaterials for triggering amplified ICD-mediated antitumor immune responses.Endoplasmic reticulum localized ICD,focused ultrasound hyper-thermia,cell membrane camouflaged nanomedicines,amplified reactive oxygen species(ROS)genera-tion,metallo-immunotherapy,ion modulators and engineered bacteria are among the most innovative approaches.Various challenges,merits and demerits of ICD inducer nanomedicines were also discussed with shedding light on the future role of this technology in improving the outcomes of cancer immuno-therapy.
查看更多>>摘要：The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unex-plored target for drug development.In this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell model.Ciclopir-ox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation.Ciclopirox induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower mobility.These condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP expression.Our results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.
查看更多>>摘要：Type Ⅰ interferon(IFN)inhibits a wide spectrum of viruses through stimulating the expres-sion of antiviral proteins.As an IFN-induced protein,myxovirus resistance B(MXB)protein was reported to inhibit multiple highly pathogenic human viruses.It remains to be determined whether MXB employs a common mechanism to restrict different viruses.Here,we find that IFN alters the subcellular localization of hundreds of host proteins,and this IFN effect is partially lost upon MXB deple-tion.The results of our mechanistic study reveal that MXB recognizes vimentin(VIM)and recruits pro-tein kinase B(AKT)to phosphorylate VIM at amino acid S38,which leads to reorganization of the VIM network and impairment of intracellular trafficking of virus protein complexes,hence causing a restric-tion of virus infection.These results highlight a new function of MXB in modulating VIM-mediated traf-ficking,which may lead towards a novel broad-spectrum antiviral strategy to control a large group of viruses that depend on VIM for successful replication.
查看更多>>摘要：The formation of new and functional cardiomyocytes requires a 3-step process:dediffer-entiation,proliferation,and redifferentiation,but the critical genes required for efficient dedifferen-tiation,proliferation,and redifferentiation remain unknown.In our study,a circular trajectory using single-nucleus RNA sequencing of the pericentriolar material 1 positive(PCM1+)cardiomyocyte nuclei from hearts 1 and 3 days after surgery-induced myocardial infarction(MI)on postnatal Day 1 was reconstructed and demonstrated that actin remodeling contributed to the dedifferentia-tion,proliferation,and redifferentiation of cardiomyocytes after injury.We identified four top actin-remodeling regulators,namely Tmsb4x,Tmsb10,Dmd,and Ctnna3,which we collectively referred to as 2D2P.Transiently expressed changes of 2D2P,using a polycistronic non-integrating lentivirus driven by Tnnt2(cardiac-specific troponin T)promoters(Tnnt2-2D2P-NIL),efficiently induced transiently proliferative activation and actin remodeling in postnatal Day 7 cardiomyocytes and adult hearts.Furthermore,the intramyocardial delivery of Tnnt2-2D2P-NIL resulted in a sus-tained improvement in cardiac function without ventricular dilatation,thickened septum,or fatal arrhythmia for at least 4 months.In conclusion,this study highlights the importance of actin remo-deling in cardiac regeneration and provides a foundation for new gene-cocktail-therapy approaches to improve cardiac repair and treat heart failure using a novel transient and cardiomyocyte-specific viral construct.
查看更多>>摘要：Oncolytic viruses(OVs),a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact,are emerging as promising living anticancer agents.Unlike traditional drugs composed of non-replicating compounds or biomolecules,the replicative nature of viruses confer unique pharmacokinetic properties that require further studies.Despite some pharmacoki-netics studies of OVs,mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague.Here,we characterized the pharmacokinetic profile of oncolytic virus M1(OVM)in immunocompetent mouse tumor models and identified the JAK-STAT pathway as a key modulator of OVM pharmacokinetics.By suppressing the JAK-STAT pathway,early OVM pharmacokinetics are ameliorated,leading to enhanced tumor-specific viral accumulation,increased AUC and Cmax,and improved antitumor efficacy.Rather than compromising antitumor immunity after JAK-STAT inhibition,the improved pharma-cokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment,providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade,such as anti-PD-L-1.Taken together,this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.
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