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1.
Org Biomol Chem ; 22(20): 4057-4061, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38716633

ABSTRACT

An efficient and practical one-pot synthesis of isoindolines from readily available starting materials was achieved under mild conditions by implementing an isoindole umpolung strategy. A variety of isoindolines were prepared with good to excellent yields. Biological screens of these identified compounds demonstrated that they are potent potentiators of colistin for multi-drug resistant Acinetobacter baumannii.


Subject(s)
Acinetobacter baumannii , Anti-Bacterial Agents , Colistin , Drug Resistance, Multiple, Bacterial , Microbial Sensitivity Tests , Acinetobacter baumannii/drug effects , Colistin/pharmacology , Colistin/chemical synthesis , Colistin/chemistry , Drug Resistance, Multiple, Bacterial/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Isoindoles/chemical synthesis , Isoindoles/pharmacology , Isoindoles/chemistry , Molecular Structure , Structure-Activity Relationship
2.
Drug Des Devel Ther ; 17: 3023-3031, 2023.
Article in English | MEDLINE | ID: mdl-37789971

ABSTRACT

This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D2, 5-hydroxytryptamine (5-HT)2A, and 5-HT7 receptors and a partial agonistic effect on the 5-HT1A receptor with low affinities for muscarinic M1, histamine H1, and a1 adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT7 and 5-HT1A receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.


Subject(s)
Antipsychotic Agents , Schizophrenia , Humans , Lurasidone Hydrochloride/adverse effects , Schizophrenia/drug therapy , Serotonin , Isoindoles/pharmacology , Thiazoles/pharmacology , Antipsychotic Agents/adverse effects , Weight Gain
3.
Chem Biol Drug Des ; 102(6): 1448-1457, 2023 12.
Article in English | MEDLINE | ID: mdl-37712451

ABSTRACT

In this study, synthesis of novel isoindole-1,3-dione analogues bearig halo, hydroxy, and acetoxy groups at the position 4,5,6 of the bicyclic imide ring was performed to examine their potential anticancer effects against some cell lines. A multistep chemical pathway was used to synthesize the derivatives. The cytotoxic effect of trisubstituted isoindole derivatives were evaluated by determining cellular viability using the MTT assay against A549, PC-3, HeLa, Caco-2, and MCF-7 cell lines. The C-2 selective ring-opening products were obtained from the ring-opening reaction of 5-alkyl/aryl-2-hydroxyhexahydro-4H-oxireno[2,3-e]isoindole-4,6(5H)-diones with nucleophiles such as chloride (Cl- ) and bromide (Br- ) ions. In addition, the ring-opening products halodiols were converted to their related acetates. The anticancer activity of synthesized isoindole-1,3-dione derivatives was investigated against HeLa, A549, MCF-7, PC3, and Caco-2 cells in vitro and resulted in varies cytotoxic effect depend on the group attached to the isoindole molecule. Furthermore, the evaluation of the antimicrobial action of trisubstituted isoindole derivatives against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria was assessed and found out selective inhibition of the both bacterial growth via different trisubstituted isoindole derivatives. The results of this work encourage further research on the potential utilization of trisubstituted isoindole derivatives as cytotoxic and antimicrobial agents.


Subject(s)
Anti-Infective Agents , Antineoplastic Agents , Humans , Caco-2 Cells , Isoindoles/chemistry , Isoindoles/pharmacology , Anti-Bacterial Agents/chemistry , Antineoplastic Agents/chemistry , Anti-Infective Agents/pharmacology , Structure-Activity Relationship , Molecular Structure
5.
J Med Chem ; 66(3): 2054-2063, 2023 02 09.
Article in English | MEDLINE | ID: mdl-36661843

ABSTRACT

Screening of 25 analogs of Ebselen, diversified at the N-aromatic residue, led to the identification of the most potent inhibitors of Sporosarcina pasteurii urease reported to date. The presence of a dihalogenated phenyl ring caused exceptional activity of these 1,2-benzisoselenazol-3(2H)-ones, with Ki value in a low picomolar range (<20 pM). The affinity was attributed to the increased π-π and π-cation interactions of the dihalogenated phenyl ring with αHis323 and αArg339 during the initial step of binding. Complementary biological studies with selected compounds on the inhibition of ureolysis in whole Proteus mirabilis cells showed a very good potency (IC50 < 25 nM in phosphate-buffered saline (PBS) buffer and IC90 < 50 nM in a urine model) for monosubstituted N-phenyl derivatives. The crystal structure of S. pasteurii urease inhibited by one of the most active analogs revealed the recurrent selenation of the Cys322 thiolate, yielding an unprecedented Cys322-S-Se-Se chemical moiety.


Subject(s)
Enzyme Inhibitors , Urease , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Bacteria/metabolism , Isoindoles/pharmacology , Azoles/pharmacology
6.
Eur J Med Chem ; 245(Pt 1): 114865, 2023 Jan 05.
Article in English | MEDLINE | ID: mdl-36335743

ABSTRACT

The development of novel therapeutics promoting selective tumor elimination is the mainstay of clinical oncology. Emerging insights into tumor targeting reveal caspases activation, especially caspase-3, as a personalized anticancer strategy. Our on-going cancer research has exploited Passerini α-acyloxy carboxamides as caspase-3/7-dependent apoptotic inducers. Herein, we adopted scaffold hopping design to introduce new series of isoindole-based Passerini adducts as caspase-3/7 activators inspired by natural alkaloids from Lion's Mane mushroom promoting caspase-3-mediated apoptosis. Additional pharmacophoric motifs of lead caspase activators were merged into the tailored Passerini skeleton. The rationally designed adducts were synthesized utilizing one-pot reaction of the novel 4-(2'-phthalimido)phenylisonitrile 5, cyclohexanone and miscellaneous carboxylic acids under Passerini conditions. All derivatives were screened for their antiproliferative activities against lung A549, colorectal Caco-2 and breast MDA-MB 231 cancer cells compared to normal fibroblasts utilizing MTT assay. Most of the evaluated derivatives were superior to 5-fluorouracil. The 2-(1H-indol-3-yl)acetate derivative (8a) recorded the highest anticancer potency (IC50 = 0.04-0.11 µM) and selectivity (SI = 42.59-125.53), followed by the 3-(4-(trifluoromethyl)phenyl)acrylate (8m), the 2-(phenylsulfonyl)glycinate (8q), and the 2-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)phenoxy)acetate (8c) derivatives, respectively. The four hits induced cancer cells apoptosis (up to 57.99%) via caspase-3/7 activation (up to 5.47 folds). Apoptosis-inducing factor1 (AIF1) quantification assay excluded their caspase-independent apoptosis induction potential via AIF1 signaling pathway. Docking simulations clarified the possible binding modes of the hit compounds with XIAP BIR2 domain; the specific receptor of caspase-3/7 activators, and aided identifying their structural determinants of activity. Finally, their practical LogP, efficiency metrics, in silico ADMET profiling were drug-like.


Subject(s)
Antineoplastic Agents , Apoptosis , Caspase 3 , Caspase 7 , Isoindoles , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Caco-2 Cells , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation , Drug Screening Assays, Antitumor , Isoindoles/chemistry , Isoindoles/pharmacology , Molecular Structure , Structure-Activity Relationship , A549 Cells
8.
Antimicrob Agents Chemother ; 66(12): e0122622, 2022 12 20.
Article in English | MEDLINE | ID: mdl-36374026

ABSTRACT

Tecovirimat is an antiviral drug initially developed against variola virus (VARV) to treat smallpox infection. Due to its mechanism of action, it has activity against the family of orthopoxviruses, including vaccinia and the human monkeypox virus (HMPXV). Efficacy studies have thus far been limited to animal models, with human safety trials showing no serious adverse events. Currently approved by the FDA only for the treatment of smallpox, tecovirimat shows promise for the treatment of HMPXV. Tecovirimat has been prescribed via an expanded access for an investigational new drug protocol during the 2022 outbreak. This review will examine the literature surrounding tecovirimat's mechanism of action, pharmacokinetics, safety, efficacy, and potential for resistance.


Subject(s)
Mpox (monkeypox) , Smallpox , Variola virus , Animals , Humans , Smallpox/drug therapy , Monkeypox virus , Antiviral Agents/adverse effects , Benzamides/pharmacology , Benzamides/therapeutic use , Isoindoles/therapeutic use , Isoindoles/pharmacology , Mpox (monkeypox)/drug therapy
9.
Nat Microbiol ; 7(12): 1951-1955, 2022 12.
Article in English | MEDLINE | ID: mdl-36344621

ABSTRACT

The ongoing monkeypox virus (MPXV) outbreak is the largest ever recorded outside of Africa. We isolated and sequenced a virus from the first clinical MPXV case diagnosed in France (May 2022). We report that tecovirimat (ST-246), a US Food and Drug Administration approved drug, is efficacious against this isolate in vitro at nanomolar concentrations, whereas cidofovir is only effective at micromolar concentrations. Our results support the use of tecovirimat in ongoing human clinical trials.


Subject(s)
Monkeypox virus , Mpox (monkeypox) , United States , Humans , Mpox (monkeypox)/drug therapy , Isoindoles/pharmacology , Isoindoles/therapeutic use , Benzamides/pharmacology , Benzamides/therapeutic use
10.
Sci Transl Med ; 14(673): eade7646, 2022 11 30.
Article in English | MEDLINE | ID: mdl-36318038

ABSTRACT

The recent emergence of the monkeypox virus (MPXV) in non-endemic countries has been designated a Public Health Emergency of International Concern by the World Health Organization. There are currently no approved treatments for MPXV infection in the United States or Canada. The antiviral drug tecovirimat (commonly called TPOXX), previously approved for smallpox treatment, is currently being deployed for treatment of MPXV infections where available based on previously accrued data. We tested the efficacy of TPOXX both in vitro and in vivo against a clade 2 Canadian 2022 isolate of MPXV isolated during the current outbreak. TPOXX prevented MPXV replication in vitro with an effective concentration in the nanomolar range. To evaluate TPOXX efficacy in vivo, we first characterized the CAST/EiJ mouse model with the same 2022 Canadian isolate. Unlike previous descriptions of this model, the Canadian isolate was not lethal in CAST/EiJ mice, although it replicated efficiently in the respiratory tract after intranasal infection. Subsequent experiments demonstrated that daily oral TPOXX treatment markedly reduced viral titers in the tissues 1 and 2 weeks after infection. Our data indicate that TPOXX is highly effective against currently circulating MPXV strains and could be an important contributor to curbing the ongoing outbreak.


Subject(s)
Monkeypox virus , Mpox (monkeypox) , Mice , Animals , Canada , Mpox (monkeypox)/drug therapy , Mpox (monkeypox)/prevention & control , Isoindoles/pharmacology , Isoindoles/therapeutic use
11.
Int J Mol Sci ; 23(18)2022 Sep 06.
Article in English | MEDLINE | ID: mdl-36142133

ABSTRACT

Microtubule-targeting agents (MTAs) are effective drugs for cancer treatment. A novel diaryl [1,2]oxazole class of compounds binding the colchicine site was synthesized as cis-restricted-combretastatin-A-4-analogue and then chemically modified to have improved solubility and a wider therapeutic index as compared to vinca alkaloids and taxanes. On these bases, a new class of tricyclic compounds, containing the [1,2]oxazole ring and an isoindole moiety, has been synthetized, among which SIX2G emerged as improved MTA. Several findings highlighted the ability of some chemotherapeutics to induce immunogenic cell death (ICD), which is defined by the cell surface translocation of Calreticulin (CALR) via dissociation of the PP1/GADD34 complex. In this regard, we computationally predicted the ability of SIX2G to induce CALR exposure by interacting with the PP1 RVxF domain. We then assessed both the potential cytotoxic and immunogenic activity of SIX2G on in vitro models of multiple myeloma (MM), which is an incurable hematological malignancy characterized by an immunosuppressive milieu. We found that the treatment with SIX2G inhibited cell viability by inducing G2/M phase cell cycle arrest and apoptosis. Moreover, we observed the increase of hallmarks of ICD such as CALR exposure, ATP release and phospho-eIF2α protein level. Through co-culture experiments with immune cells, we demonstrated the increase of (i) CD86 maturation marker on dendritic cells, (ii) CD69 activation marker on cytotoxic T cells, and (iii) phagocytosis of tumor cells following treatment with SIX2G, confirming the onset of an immunogenic cascade. In conclusion, our findings provide a framework for further development of SIX2G as a new potential anti-MM agent.


Subject(s)
Antineoplastic Agents , Multiple Myeloma , Vinca Alkaloids , Humans , Adenosine Triphosphate/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Calreticulin/metabolism , Cell Line, Tumor , Colchicine/pharmacology , Immunogenic Cell Death , Isoindoles/pharmacology , Microtubules/metabolism , Multiple Myeloma/drug therapy , Oxazoles/pharmacology , Taxoids/pharmacology , Vinca Alkaloids/pharmacology , Pemetrexed/pharmacology , Pemetrexed/therapeutic use
12.
Proc Natl Acad Sci U S A ; 119(30): e2201208119, 2022 07 26.
Article in English | MEDLINE | ID: mdl-35858434

ABSTRACT

Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded, RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to define the interactome of LASV polymerase in cells under conditions that recreate LASV RNA synthesis. We engineered a LASV polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity and successfully biotinylated the proximal proteome, which allowed the identification of 42 high-confidence LASV polymerase interactors. We subsequently performed a small interfering RNA (siRNA) screen to identify those interactors that have functional roles in authentic LASV infection. As proof of principle, we characterized eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we found to be a proviral factor that physically associates with LASV polymerase. Targeted degradation of GSPT1 by a small-molecule drug candidate, CC-90009, resulted in strong inhibition of LASV infection in cultured cells. Our work demonstrates the feasibility of using proximity proteomics to illuminate and characterize yet-to-be-defined host-pathogen interactome, which can reveal new biology and uncover novel targets for the development of antivirals against highly pathogenic RNA viruses.


Subject(s)
Acetamides , Antiviral Agents , Isoindoles , Lassa virus , Peptide Termination Factors , Piperidones , RNA-Dependent RNA Polymerase , Viral Proteins , Acetamides/pharmacology , Acetamides/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Cell Line, Tumor , Humans , Isoindoles/pharmacology , Isoindoles/therapeutic use , Lassa Fever/drug therapy , Lassa virus/drug effects , Peptide Termination Factors/metabolism , Piperidones/metabolism , Piperidones/pharmacology , Piperidones/therapeutic use , Protein Interaction Maps/drug effects , Proteolysis/drug effects , Proteome , Proteomics , RNA-Dependent RNA Polymerase/metabolism , Viral Proteins/metabolism
13.
Drug Dev Res ; 83(6): 1331-1341, 2022 09.
Article in English | MEDLINE | ID: mdl-35749723

ABSTRACT

A series of [1,2]oxazolo[5,4-e]isoindole derivatives was evaluated against HL-60 cell line and its multidrug resistance (MDR) variant, HL-60R, resistant to doxorubicin and to other P-gp substrates by overexpressing the efflux pump. They displayed antiproliferative activities, with IC50 values ranging from 0.02 to 5.5 µM. In particular, the newly synthesized compound 4k produced synergistic effects in terms of cell growth inhibition and cell death induction either in combination with a Vinca alkaloid, Vinblastine, and a Taxane, Paclitaxel in HL-60R cells. The study of the mechanism of action indicated that all compounds showed antimitotic activity through inhibition of tubulin polymerization. Thus, [1,2]oxazoles could represent a valuable tool to overcome MDR mechanism, confirming the potential use of this class of compounds.


Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , Isoindoles/pharmacology , Leukemia, Myeloid, Acute/drug therapy
14.
Neuropsychopharmacol Rep ; 42(3): 374-376, 2022 09.
Article in English | MEDLINE | ID: mdl-35508301

ABSTRACT

In this case report, an adolescent boy with sophophobia (fear of learning) is reported. Although psychoeducation about the condition was helpful to the patient, there was only a limited effect on his symptoms. Psychotropic treatment with escitalopram was initiated. He showed gradual improvement with this treatment, and there was only a limited effect on his symptoms. Hence, the patient was referred for psychotherapy, although he was unable to attend sessions. Augmentation with perospirone resulted in significant improvement. Research about pharmacological approaches to treat childhood and adolescent phobias is limited and requires further investigation.


Subject(s)
Escitalopram , Isoindoles , Adolescent , Child , Fear , Humans , Isoindoles/pharmacology , Isoindoles/therapeutic use , Male , Thiazoles/pharmacology , Thiazoles/therapeutic use
15.
Mol Cell Biochem ; 477(6): 1873-1885, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35338455

ABSTRACT

Renal ischemia-reperfusion (I/R) injury is one of the most common causes of chronic kidney disease (CKD). It brings unfavorable outcomes to the patients and leads to a considerable socioeconomic burden. The study of renal I/R injury is still one of the hot topics in the medical field. Ebselen is an organic selenide that attenuates I/R injury in various organs. However, its effect and related mechanism underlying renal I/R injury remains unclear. In this study, we established a rat model of renal I/R injury to study the preventive effect of ebselen on renal I/R injury and further explore the potential mechanism of its action. We found that ebselen pretreatment reduced renal dysfunction and tissue damage caused by renal I/R. In addition, ebselen enhanced autophagy and inhibited oxidative stress. Additionally, ebselen pretreatment activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The protective effect of ebselen was suppressed by autophagy inhibitor wortmannin. In conclusion, ebselen could ameliorate renal I/R injury, probably by enhancing autophagy, activating the Nrf2 signaling pathway, and reducing oxidative stress.


Subject(s)
NF-E2-Related Factor 2 , Reperfusion Injury , Animals , Autophagy , Humans , Isoindoles/pharmacology , NF-E2-Related Factor 2/metabolism , Organoselenium Compounds , Oxidative Stress , Rats , Reperfusion Injury/metabolism
16.
J Biochem Mol Toxicol ; 36(5): e23015, 2022 May.
Article in English | MEDLINE | ID: mdl-35257437

ABSTRACT

In this study, novel hybrid isoindole-1,3(2H)-dione compounds (10 and 11) carrying a 1H-tetrazole moiety were synthesized, characterized and their inhibitory properties against xanthine oxidase (XO) and carbonic anhydrase isoenzymes (hCA I and hCA II) were investigated. Allopurinol for XO and acetazolamide for carbonic anhydrase isoenzymes were used as positive standards in inhibition studies. In addition, compounds 8 and 9, which were obtained in the intermediate step, were also investigated for their inhibition effects against the three enzymes. According to the enzyme inhibition results, hybrid isoindole-1,3(2H)-dione derivatives 10 and 11 showed significant inhibitory effects against all three enzymes. Surprisingly, compound 8, containing a SCN functional group, exhibited a greater inhibitory effect than the other compounds against hCA I and hCA II. The IC50 values of compound 8 against hCA I and hCA II were found to be 3.698 ± 0.079 and 3.147 ± 0.083 µM, respectively. Compound 8 (IC50 = 4.261 ± 0.034 µM) showed higher activity than allopurinol (IC50 = 4.678 ± 0.029 µM) and the other compounds against XO, as well. These results clearly show the effect of the SCN group on the inhibition. In addition, in silico molecular docking studies were performed to understand the molecular interactions between each compound and enzymes, and the results were evaluated.


Subject(s)
Carbonic Anhydrase Inhibitors , Carbonic Anhydrases , Allopurinol , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Isoenzymes , Isoindoles/pharmacology , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Tetrazoles
17.
Dalton Trans ; 51(11): 4466-4476, 2022 Mar 15.
Article in English | MEDLINE | ID: mdl-35229854

ABSTRACT

The emergence of nanoscience and its effect on the development of diverse scientific fields, particularly materials chemistry, are well known today. In this study, a new di-substituted phthalonitrile derivative, namely 4,5-bis((4-(dimethylamino)phenyl)ethynyl)phthalonitrile (1), and its octa-substituted metal phthalocyanines {M = Co (2), Zn (3)} were prepared. All the newly synthesized compounds were characterized using a number of spectroscopic approaches, including FT-IR, mass, NMR, and UV-vis spectroscopy. The resultant compounds modified the surface of the gold nanoparticles (NG-1-3). Characterization of the newly synthesized conjugates was carried out by transmission electron microscopy. The antioxidant activity of compounds 1-3, NG-1-3, and NG was evaluated using the DPPH scavenging process and the highest radical scavenging activity was obtained with compounds 1, NG-1, 2, and NG-2 (100%). The antimicrobial activity of compounds 1-3, NG-1-3, and NG was studied using a microdilution assay and the most effective antimicrobial activity was obtained for NG-3 against all the tested microorganisms. The newly synthesized compounds demonstrated high DNA cleavage activity. Compounds 1-3, NG-1-3, and NG significantly inhibited the microbial cell viability of E. coli and exhibited perfect antimicrobial photodynamic therapeutic activity with 100% inhibition after 20 min LED irradiation. Besides, the biofilm inhibition activity of compounds 1-3, NG-1-3, and NG on the growth of S. aureus and P. aeruginosa were examined and compounds 1-3 and NG-1-3, especially NG-1-3, displayed high biofilm inhibition activities.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antioxidants/pharmacology , Coordination Complexes/pharmacology , Escherichia coli/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antioxidants/chemical synthesis , Antioxidants/chemistry , Biphenyl Compounds/antagonists & inhibitors , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Isoindoles/chemistry , Isoindoles/pharmacology , Metal Nanoparticles , Metals, Heavy/chemistry , Metals, Heavy/pharmacology , Microbial Sensitivity Tests , Picrates/antagonists & inhibitors
18.
J Biol Chem ; 298(3): 101612, 2022 03.
Article in English | MEDLINE | ID: mdl-35065969

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons progressively and rapidly degenerate, eventually leading to death. The first protein found to contain ALS-associated mutations was copper/zinc superoxide dismutase 1 (SOD1), which is conformationally stable when it contains its metal ligands and has formed its native intramolecular disulfide. Mutations in SOD1 reduce protein folding stability via disruption of metal binding and/or disulfide formation, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS; however, the results have been mixed. Here, we utilize a small-molecule polytherapy of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuATSM) and ebselen to mimic the metal delivery and disulfide bond promoting activity of the cellular chaperone of SOD1, the "copper chaperone for SOD1." Using microscopy with automated image analysis, we find that polytherapy using CuATSM and ebselen is highly effective and acts in synergy to reduce inclusion formation in a cell model of SOD1 aggregation for multiple ALS-associated mutants. Polytherapy reduces mutant SOD1-associated cell death, as measured by live-cell microscopy. Measuring dismutase activity via zymography and immunoblotting for disulfide formation showed that polytherapy promoted more effective maturation of transfected SOD1 variants beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may merit more study as an effective method of treating SOD1-associated ALS.


Subject(s)
Amyotrophic Lateral Sclerosis , Organocopper Compounds , Superoxide Dismutase-1 , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Biomimetic Materials/pharmacology , Copper/metabolism , Disulfides/chemistry , Humans , Isoindoles/pharmacology , Molecular Chaperones/metabolism , Mutation , Organocopper Compounds/pharmacology , Organoselenium Compounds/pharmacology , Protein Folding/drug effects , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism
19.
Biochem Biophys Res Commun ; 591: 82-87, 2022 02 05.
Article in English | MEDLINE | ID: mdl-34999258

ABSTRACT

Steroid hormone synthesis in steroidogenic cells requires cholesterol (Ch) delivery to/into mitochondria via StAR family trafficking proteins. In previous work, we discovered that 7-OOH, an oxidative stress-induced cholesterol hydroperoxide, can be co-trafficked with Ch, thereby causing mitochondrial redox damage/dysfunction. We now report that exposing MA-10 Leydig cells to Ch/7-OOH-containing liposomes (SUVs) results in (i) a progressive increase in fluorescence probe-detected lipid peroxidation in mitochondrial membranes, (ii) a reciprocal decrease in immunoassay-detected progesterone generation, and ultimately (iii) loss of cell viability with increasing 7-OOH concentration. No significant effects were observed with a phospholipid hydroperoxide over the same concentration range. Glutathione peroxidase GPx4, which can catalyze lipid hydroperoxide detoxification, was detected in mitochondria of MA-10 cells. Mitochondrial lipid peroxidation and progesterone shortfall were exacerbated when MA-10 cells were treated with Ch/7-OOH in the presence of RSL3, a GPx4 inhibitor. However, Ebselen, a selenoperoxidase mimetic, substantially reduced RSL3's negative effects, thereby partially rescuing the cells from peroxidative damage. These findings demonstrate that co-trafficking of oxidative stress-induced 7-OOH can disable steroidogenesis, and that GPx4 can significantly protect against this.


Subject(s)
Cholesterol/analogs & derivatives , Leydig Cells/metabolism , Lipid Peroxidation , Mitochondria/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Steroids/metabolism , Animals , Carbolines/pharmacology , Cell Death/drug effects , Cell Line, Tumor , Cholesterol/metabolism , Fluorescence , Isoindoles/pharmacology , Leydig Cells/drug effects , Lipid Peroxidation/drug effects , Male , Mice , Mitochondria/drug effects , Mitochondrial Membranes/drug effects , Mitochondrial Membranes/metabolism , Organoselenium Compounds/pharmacology , Phosphatidylcholines/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/antagonists & inhibitors , Progesterone/biosynthesis , Protective Agents/pharmacology
20.
Nucleic Acids Res ; 50(3): 1484-1500, 2022 02 22.
Article in English | MEDLINE | ID: mdl-35037045

ABSTRACT

The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14-nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14-nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14-nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3'-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14-nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12-nsp7-nsp8 (nsp12-7-8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14-nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14-nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.


Subject(s)
Antiviral Agents/pharmacology , Drug Evaluation, Preclinical , Exoribonucleases/metabolism , Genome, Viral/genetics , Genomic Instability , SARS-CoV-2/enzymology , SARS-CoV-2/genetics , Viral Nonstructural Proteins/metabolism , Viral Regulatory and Accessory Proteins/metabolism , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Exoribonucleases/antagonists & inhibitors , Genome, Viral/drug effects , Genomic Instability/drug effects , Genomic Instability/genetics , HIV Integrase Inhibitors/pharmacology , Isoindoles/pharmacology , Multienzyme Complexes/antagonists & inhibitors , Multienzyme Complexes/metabolism , Organoselenium Compounds/pharmacology , RNA, Viral/biosynthesis , RNA, Viral/genetics , Raltegravir Potassium/pharmacology , SARS-CoV-2/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Regulatory and Accessory Proteins/antagonists & inhibitors , Virus Replication/drug effects , Virus Replication/genetics
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