RESUMO
Remarkable progress has been made in the development of cysteine-targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e. lysine, or K) have emerged in recent years. Besides a highly conserved catalytic lysine, almost all human protein kinases possess an equally conserved glutamate/aspartate (e.g. E/D) that forms a K-E/D salt bridge within the enzyme's active site. Electrophilic ynamides were previously used as effective peptide coupling reagents and to develop E/D-targeting covalent protein inhibitors/probes. In the present study, we report the first ynamide-based small-molecule inhibitors capable of inducing intramolecular cross-linking of various protein kinases, leading to subsequent irreversible inhibition of kinase activity. Our strategy took advantage of the close distance between the highly conserved catalytic K and E/D residues in a targeted kinase, thus providing a conceptually general approach to achieve irreversible kinase inhibition with high specificity and desirable cellular potency. Finally, this ynamide-facilitated, ligand-induced mechanism leading to intramolecular kinase cross-linking and inhibition was unequivocally established by using recombinant ABL kinase as a representative.
Assuntos
Inibidores de Proteínas Quinases , Bibliotecas de Moléculas Pequenas , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Reagentes de Ligações Cruzadas/química , Proteínas Quinases/metabolismo , Proteínas Quinases/química , Estrutura Molecular , Amidas/química , Amidas/farmacologiaRESUMO
Advances in targeted covalent inhibitors (TCIs) have been made by using lysine-reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell-active TCIs are however available. We report herein lysine-reactive activity-based probes (ABPs; 2-14) based on the chemistry of aryl fluorosulfates (ArOSO2 F) capable of global reactivity profiling of the catalytic lysine in human kinome from mammalian cells. We concurrently developed reversible covalent ABPs (15/16) by installing salicylaldehydes (SA) onto a promiscuous kinase-binding scaffold. The stability and amine reactivity of these probes exhibited a broad range of tunability. X-ray crystallography and mass spectrometry (MS) confirmed the successful covalent engagement between ArOSO2 F on 9 and the catalytic lysine of SRC kinase. Chemoproteomic studies enabled the profiling of >300 endogenous kinases, thus providing a global landscape of ligandable catalytic lysines of the kinome. By further introducing these aminophiles into VX-680 (a noncovalent inhibitor of AURKA kinase), we generated novel lysine-reactive TCIs that exhibited excellent in vitro potency and reasonable cellular activities with prolonged residence time. Our work serves as a general guide for the development of lysine-reactive ArOSO2 F-based TCIs.
Assuntos
Lisina , Fosfotransferases , Animais , Humanos , Lisina/química , Ligação Proteica , Espectrometria de Massas , Catálise , Mamíferos/metabolismoRESUMO
Lysine-targeting irreversible covalent inhibitors have attracted growing interests in recent years, especially in the fields of kinase research. Despite encouraging progress, few chemistries are available to develop inhibitors that are exclusively lysine-targeting, selective, and cell-active. We report herein a 2-ethynylbenzaldehyde (EBA)-based, lysine-targeting strategy to generate potent and selective small-molecule inhibitors of ABL kinase by selectively targeting the conserved catalytic lysine in the enzyme. We showed the resulting compounds were cell-active, capable of covalently engaging endogenous ABL kinase in K562 cells with long-residence time and few off-targets. We further validated the generality of this strategy by developing EBA-based irreversible inhibitors against EGFR (a kinase) and Mcl-1 (a nonkinase) that covalently reacted with the catalytic and noncatalytic lysine within each target.
RESUMO
A method for the electrochemical diastereoselective oxytrifluoromethylation of indoles was developed for the eco-friendly synthesis of CF3-containing spirocyclic indolines. The cascade reaction comprised anodic oxidation to obtain CF3 radicals, the addition of radicals to indoles, and intramolecular spirocyclization. The reaction system without external chemical oxidants could easily be scaled up. Antiproliferation assays of these CF3-substituted spirocyclic indolines exhibited their promising activities and selectivities toward several types of cancer cells, including Huh-7, A549, and cisplatin-resistant cancer cells (A549/DDP).
Assuntos
Indóis , Oxidantes , Indóis/química , OxirreduçãoRESUMO
Parkinson's disease (PD), as the second most common neurodegenerative disease, is caused by complex pathological processes and currently remains very difficult to treat. PD brings great distress to patients and imposes a heavy economic burden on society. The number of PD patients is growing as the aging population increases worldwide. Therefore, it is crucial to develop new tools for aiding the early diagnosis and treatment of PD. The significant pathological features involved in PD include the abnormal accumulation of α-synuclein, metal ion dyshomeostasis, oxidative stress, mitochondrial dysfunction and neurotransmitter deficiencies. In recent years, fluorescent probes have emerged as a powerful bioimaging tool with potential to help understand the pathological processes of PD via the detection and monitoring of pathological features. In this review, we comprehensively summarize the design and working mechanisms of fluorescent probes along with their applications in the detection of various PD biomarkers. We also discuss the current limitations of fluorescent probes and provide perspectives on how these limitations can be overcome to develop better fluorescent probes suitable for application in clinical trials in the future. We hope that this review provides valuable information and guidance for the development of new fluorescent probes that can be used clinically in the early diagnosis of PD and contributes to the development of efficient PD drugs in the future.
Assuntos
Corantes Fluorescentes/química , Imagem Óptica , Doença de Parkinson/diagnóstico , Biomarcadores/análise , Células HEK293 , Humanos , Estrutura MolecularRESUMO
Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.
Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Células K562 , Lisina/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologiaRESUMO
Mitochondrion is a promising target in cancer therapy. However, gaining access to this organelle is difficult due to the obstacles to cross the complicated mitochondrial membrane. Cell-penetrating peptides (CPPs) with mitochondrion-targeting ability, named mitochondrion-targeting peptides (MTPs), are efficient tools to deliver exogenous therapeutics into mitochondria. Herein, we report several new MTPs, which can be readily synthesized via resin-based solid-phase peptide synthesis. In particular, MTP3 (compound 5), consisting of three positively charged arginines and two D- and L- alternating naphthylalanines, demonstrated excellent mitochondrion-targeting ability with high Pearson's correlation coefficient, suggesting that MTP3 has good potential for mitochondrion-targeted drug delivery. As proof-of-concept, the feasibility of MTP3 was validated by the preparation of a mitochondrion-targeting prodrug (compound 17, doxorubicin-based prodrug). This prodrug was subsequently confirmed to be specifically transported to the mitochondria of tumor cells, where it was able to release the native doxorubicin upon intracellular GSH activation, leading to mitochondrial depolarization and eventually cell death. Importantly, compound 17 showed good cytotoxicity against human tumor cells while negligible toxicity towards normal cells, indicating its potential as a potent mitochondrial medicine for targeted cancer therapy. Our study thus opens a way for engineered CPPs to be used to deliver bioactive cargos in mitochondrion-targeted cancer therapy.
Assuntos
Peptídeos Penetradores de Células , Neoplasias , Preparações Farmacêuticas , Sistemas de Liberação de Medicamentos , Humanos , Mitocôndrias , Neoplasias/tratamento farmacológicoRESUMO
Mitochondria are key organelles that perform vital cellular functions such as those related to cell survival and death. The targeted delivery of different types of cargos to mitochondria is a well-established strategy to study mitochondrial biology and diseases. Of the various existing mitochondrion-transporting vehicles, most suffer from poor cytosolic entry, low delivery efficiency, limited cargo types, and cumbersome preparation protocols, and none was known to be universally applicable for mitochondrial delivery of different types of cargos (small molecules, proteins, and nanomaterials). Herein, two new cell-penetrating, mitochondrion-targeting ligands (named MitoLigand ) that are capable of effectively "tagging" small-molecule drugs, native proteins and nanomaterials are disclosed, as well as their corresponding chemoselective conjugation chemistry. Upon successful cellular delivery and rapid endosome escape, the released native cargos were found to be predominantly localized inside mitochondria. Finally, by successfully delivering doxorubicin, a well-known anticancer drug, to the mitochondria of HeLa cells, we showed that the released drug possessed potent cell cytotoxicity, disrupted the mitochondrial membrane potential and finally led to apoptosis. Our strategy thus paves the way for future mitochondrion-targeted therapy with a variety of biologically active agents.
Assuntos
Peptídeos Penetradores de Células , Nanoestruturas , Sistemas de Liberação de Medicamentos , Células HeLa , Humanos , Ligantes , MitocôndriasRESUMO
Polymyxin B (PMB) is a small cyclic polycationic lipopeptide, which can be used as an antibiotic drug against Gram-negative bacteria. In this work, the interaction between citrate capped silver nanoparticles (AgNPs) and PMB is studied. Experimental results show that the association constant is extremely high and the binding event leads to a significant variation in the localized surface plasmon resonance (LSPR) of AgNPs. Moreover, the PMB-AgNP colloidal system can be further exploited as a sensitive analytical platform. Taking lipopolysaccharide (LPS) as an example, we demonstrate a facile colorimetric LPS detection method. LPS is a major constituent of the Gram-negative bacterial cell wall which is used as an optimal biomarker for some diseases like urinary tract infections and sepsis. In this study, target LPS is able to tightly bind to PMB, which effectively inhibits the PMB induced aggregation of AgNPs. By monitoring the UV-vis absorption spectra, the LPS concentration can be quantitatively determined with high sensitivity. The sensing strategy is quite simple, which allows effortless diagnosis of many diseases at different stages.
RESUMO
Small molecules with free thiol groups always show high binding affinity to quantum dots (QDs). However, it is still highly challenging to detect the binding capacity between thiol-containing molecules and QDs inside a capillary. To conquer this limitation, a capillary electrophoresis with fluorescence detection (CE-FL) based assay was proposed and established to investigate the binding capacity between QDs and a poly-thiolated peptide (ATTO 590-DDSSGGCCPGCC, ATTO-C4). Interestingly, the results showed that interval time had a great influence on QDs and ATTO-C4 self-assembly, which can be attributed to longer interval time benefitting the binding of QDs to ATTO-C4. The stability assays on ATTO-C4-QD assembly indicated that high concentration of imidazole or GSH had a high capability of competing with the bound ATTO-C4, evidenced by dramatically dropping of S 625/S 565 ratio from 0.78 to 0.30 or 0.29. Therefore, all these results above suggested that this novel CE-FL based detection assay could be successfully applied to the binding studies between QDs and thiol-containing biomolecules.
RESUMO
Nowadays, despite numerous techniques available for the detection of antibody-peptide binding, sensitivity and detection limit inflow still remains a major challenge. Herein, we report a strategy for the detection of binding inflow of monoclonal anti-FLAG M2 antibody and 5,6-carboxyfluorescein-labeled FLAG tag in capillary. Antibody and peptides were sequentially injected into the capillary where they mixed and bound together. Capillary electrophoresis with fluorescence detection was employed to monitor the binding process, and the results showed that the efficacy of the antibody-peptide binding in capillary (in-capillary assay) is affected by the stoichiometry. Compared to the out-capillary assay, this novel assay showed different KD values and required a very short detection time, thus showing great potential for rapid detection as well as other applications. Additionally, our novel assay can be used to investigate the stability of the antibody-peptide complex. The addition of excess DYKDDDDK or TAMRA-DYKDDDDK, with similar binding priorities with M2, can leads to dissociation of the complex with a two-step mechanism including dissociation and association. We believed that our developed method can be extended to monitor wide range of other biomolecule interactions.
Assuntos
Anticorpos Monoclonais/química , Eletroforese Capilar/métodos , Peptídeos/química , Fluorescência , Ligação Proteica , Espectrometria de FluorescênciaRESUMO
Herein, a novel assay has been developed for monitoring PreScission protease (His-PSP) mediated enzyme cleavage of ATTO 590 labeled peptide substrate (ATTO-LEV). This novel method is based on combining the use of capillary electrophoresis and fluorescence detection (CE-FL) to dynamically monitor the enzyme cleavage activity. A multivalent peptide substrate was first constructed by immobilizing His-tagged ATTO 590 labeled peptide substrate (ATTO-LEVH6) onto the surface of CdSe/ZnS quantum dots (QDs). Once successfully immobilized, the novel multivalent peptide substrate resulted in the Förster resonance energy transfer (FRET) from QDs to ATTO 590. The ATTO-LEVH6-QD assembly was then incubated with His-PSP to study the proteolytic cleavage of surface bound ATTO-LEVH6 by CE-FL. Our data suggests that PreScission-mediated proteolytic cleavage is enzyme concentration- and incubation time-dependent. By combining capillary electrophoresis, QDs and FRET, our study herein not only provides a new method for the detection and dynamically monitoring of PSP enzyme cleavage activity, but also can be extended to the detection of many other enzymes and proteases.
Assuntos
Eletroforese Capilar/métodos , Peptídeo Hidrolases/química , Peptídeos/química , Pontos Quânticos/química , Proteínas Virais/química , Transferência Ressonante de Energia de Fluorescência/métodos , Corantes Fluorescentes/química , Proteólise , Rhinovirus/enzimologiaRESUMO
As is well known, quantum dots (QDs) have become valuable probes for cancer imaging. In particular, QD-labeled targeting peptides are capable of identifying cancer or tumors cells. A new colorectal cancer targeting peptide, cyclo(1, 9)-CTPSPFSHC, has strong targeting ability and also shows great potential in the identification and treatment of colon cancer. Herein, we synthesized a dual functional polypeptide, cyclo(1, 9)-CTPSPFSHCD2 G2 DP9 G3 H6 (H6 -TCP), to investigate its interaction with QDs inside the capillary. Fluorescence-coupled CE was adopted and applied to characterize the self-assembly of H6 -TCP onto QDs. It was indicated that the formation of the assembly was affected by H6 -TCP/QD molar ratio and sampling time. This novel in-capillary assay greatly reduced the sample consumption and the detection time, which was beneficial for the environment. It is expected that this kind of detection method could find more applications to provide more useful information for cancer diagnosis and detection of harm and hazardous substances/organisms in the environment in the future.
Assuntos
Neoplasias Colorretais/diagnóstico , Eletroforese Capilar/métodos , Sondas Moleculares/química , Neoplasias Colorretais/patologia , Fluorescência , Histidina , Humanos , Oligopeptídeos , Peptídeos/química , Pontos Quânticos/químicaRESUMO
Polyhistidine peptides are effective ligands to coat quantum dots (QDs). It is known that both the number of histidine (His) residues repeats and their structural arrangements in a peptide ligand play important roles in the assembly of the peptide onto CdSe/ZnS QDs. However, due to steric hindrance, a peptide sequence with more than six His residue tandem repeats would hardly coordinate well with Zn(2+) in the QD shell to further enhance the binding affinity. To solve this problem, a His-containing peptide ligand, ATTO 590-E2 G (NH)6 (ATTO-NH), was specifically designed and synthesized for assembly with QDs. With sequential injection of QDs and ATTO-NH into the capillary electrophoresis with fluorescence detection, strong Förster resonance energy transfer phenomenon between the QDs and the ATTO 590 dye was observed, indicating efficient self-assembly of the novel peptide onto the QDs to form ATTO-NH capped QDs inside the capillary. The binding stability of the ligand onto the QD was then systematically investigated by titrating with imidazole, His, and a his-tag containing competitive peptide. It is believed that this new in-capillary assay significantly reduced the sample consumption and the analysis time. By functionalizing QDs with certain metal cation-specific group fused peptide ligand, the QD-based probes could be even extended to the online detection of metal cations for monitoring environment in the future.
Assuntos
Eletroforese Capilar/métodos , Peptídeos/química , Pontos Quânticos , Cátions , Transferência Ressonante de Energia de Fluorescência , Compostos Heterocíclicos de 4 ou mais Anéis , Histidina , Ligantes , Metais/análiseRESUMO
The binding profile of a known inhibitor, benzenesulfonamide, against a family of carbonic anhydrase isozymes was efficiently enhanced via high-throughput screening of customized combinatorial one-bead-one-compound peptide libraries modified with the inhibitor molecule. The screening of the conjugate libraries recognized subtle variations in the microenvironments of the target enzyme and thus facilitated the identification of short peptide sequences that bind selectively to a close proximity of the active site. The identified peptide portions contributed significantly to the overall binding of the conjugate peptides with greatly enhanced affinity as well as improved specificity towards the target isozyme. The interactions between the inhibitors and the isozymes were validated by surface plasmon resonance (SPR), pull-down assay and enzymatic activity measurement. This high-throughput approach proved useful and efficient to enhance the binding profile of known inhibitors and may apply to developing effective inhibitors for a wide range of isozyme families.
Assuntos
Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Biblioteca de Peptídeos , Ligação Proteica , BenzenossulfonamidasRESUMO
Mesoporous materials have recently gained much attention owing to their large surface area, narrow pore size distribution, and superior pore structure. These materials have been demonstrated as excellent solid supports for immobilization of a variety of proteins and enzymes for their potential applications as biocatalysts in the chemical and pharmaceutical industries. However, the lack of efficient and reproducible methods for immobilization has limited the activity and recyclability of these biocatalysts. Furthermore, the biocatalysts are usually not robust owing to their rapid denaturation in bulk solvents. To solve these problems, we designed a novel hybrid material system, mesoporous silica immobilized with NiO nanoparticles (SBA-NiO), wherein enzyme immobilization is directed to specific sites on the pore surface of the material. This yielded the biocatalytic species with higher activity than free enzyme in solution. These biocatalytic species are recyclable with minimal loss of activity after several cycles, demonstrating an advantage over free enzymes.
Assuntos
Enzimas Imobilizadas/química , Óxido Nítrico/química , Dióxido de Silício/química , Adsorção , Nanopartículas/químicaRESUMO
Biological soil crust (biocrust) is widely distributed on the Loess Plateau and plays multiple roles in regulating ecosystem stability and multifunctionality. Few reports are available on the distribution characteristics of biocrust in this region, which limits the assessment of its ecological functions. Based on 388 sampling points in different precipitation zones on the Loess Plateau from 2009 to 2020, we analyzed the coverage, composition, and influencing factors of biocrust across different durations since land abandonment, precipitation levels, topography (slope aspect and position), and utilization of abandoned slopelands (shrubland, forest, and grassland). On this base, with the assistance of machine learning and spatial modeling methods, we generated a distribution map of biocrust and its composition at a resolution of 250 m × 250 m, and analyzed the spatial distribution of biocrust on the Loess Plateau. The results showed that the average biocrust coverage in the woodlands and grasslands was 47.3%, of which cyanobacterial crust accounted for 25.5%, moss crust 19.7%, and lichen crust 2.1%. There were significant temporal and spatial variations. Temporally, the coverage of biocrust in specific regions fluctuated with the extension of the abandoned durations and coverage of cyanobacterial crust, while moss crust showed a reverse pattern. In addition, the coverage of biocrust in the wet season was slightly higher than that in the dry season within a year. Spatially, the coverage of biocrusts on the sandy lands area on the Loess Plateau was higher and dominated by cyanobacterial crusts, while the coverage was lower in the hilly and gully area. Precipitation and utilization of abandoned land were the major factors driving biocrust coverage and composition, while slope direction and position did not show obvious effect. In addition, soil organic carbon content, pH, and texture were related to the distribution of biocrust. This study uncovered the spatial and temporal variability of biocrust distribution, which might provide important data support for the research and management of biocrust in the Loess Plateau region.
Assuntos
Ecossistema , Florestas , Líquens , Solo , Análise Espaço-Temporal , China , Solo/química , Líquens/crescimento & desenvolvimento , Pradaria , Cianobactérias/crescimento & desenvolvimento , Microbiologia do Solo , Altitude , Monitoramento Ambiental , Briófitas/crescimento & desenvolvimento , Árvores/crescimento & desenvolvimentoRESUMO
5-aminolevulinic acid (ALA) is a clinically approved prodrug involved in intracellular Heme biosynthesis to produce the natural photosensitizer (PS) Protoporphyrin IX (PpIX). ALA based photodynamic therapy (PDT) has been used to treat various malignant and non-malignant diseases. However, natural ALA has disadvantages such as weak lipophilicity, low stability and poor bioavailability, greatly reducing its clinical performance. The emerging nanotechnology is expected to address these limitations and thus improve the therapeutic outcomes. Herein, we summarized important recent advances in the design of ALA-based prodrugs using nanotechnology to improve the efficacy of PDT. The potential limitations and future perspectives of ALA-based nanomedicines are also briefly presented and discussed.
RESUMO
IMPORTANCE: In the unicellular parasites Leishmania spp., the etiological agents of leishmaniasis, a complex infectious disease that affects 98 countries in 5 continents, chemical inhibition of HSP90 protein leads to differentiation from promastigote to amastigote stage. Recent studies indicate potential role for protein phosphorylation in the life cycle control of Leishmania. Also, recent studies suggest a fundamentally important role of RNA-binding proteins (RBPs) in regulating the downstream effects of the HSP90 inhibition in Leishmania. Phosphorylation-dephosphorylation dynamics of RBPs in higher eukaryotes serves as an important on/off switch to regulate RNA processing and decay in response to extracellular signals and cell cycle check points. In the current study, using a combination of highly sensitive TMT labeling-based quantitative proteomic MS and robust phosphoproteome enrichment, we show for the first time that HSP90 inhibition distinctively modulates global protein phosphorylation landscapes in the different life cycle stages of Leishmania, shedding light into a crucial role of the posttranslational modification in the differentiation of the parasite under HSP90 inhibition stress. We measured changes in phosphorylation of many RBPs and signaling proteins including protein kinases upon HSP90 inhibition in the therapeutically relevant amastigote stage. This work provides insights into the importance of HSP90-mediated protein cross-talks and regulation of phosphorylation in Leishmania, thus significantly expanding our knowledge of the posttranslational modification in Leishmania biology.
Assuntos
Leishmania mexicana , Leishmania , Leishmania mexicana/metabolismo , Proteômica , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Leishmania/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Proteoma/metabolismoRESUMO
Autophagy induced by nanomaterials is one of the intracellular catabolic pathways that degrade and recycle the biomacromolecules and damaged organelles in cells and has emerged as a very promising pharmacological target critical to future drug development and anti-cancer therapy. Herein, we developed mesopore-encaged highly-dispersed active cluster-like MnOx in nanosilica entitled MnO-MS, with a size of around 130 nm. Our studies show that MnO-MS could not only obviously induce autophagy in both stable GFP-LC3 HeLa cells and GFP-LC3-mCherry HeLa cells but also could selectively inhibit lung cancer A549 cell growth at 11.19 µg mL-1 (IC50) while exhibiting little cytotoxicity in normal cells. Encouraged by these interesting results, a further mechanistic study reveals that reactive oxygen species (ROS) were excited by the active MnOx in nanosilica, leading to the disruption of mitochondrial membrane potential (MMP), enhancement of ATG5A/ATG16L/ATG4B/Beclin1, and finally, inhibition of the mTOR signaling pathways. Collectively, these findings indicate that MnO-MS-induced cell death via autophagy pathways in cancer cells. Furthermore, MnO-MS significantly inhibited tumor growth with minimal side effects in vivo, and it is envisioned that MnO-MS can be further developed as a potential autophagy inducer for the treatment of lung cancers.