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1.
NPJ Vaccines ; 7(1): 163, 2022 Dec 16.
Article in English | MEDLINE | ID: mdl-36526627

ABSTRACT

Two malaria parasite species, Plasmodium falciparum (Pf) and P. vivax (Pv) are responsible for most of the disease burden caused by malaria. Vaccine development against this disease has focused mainly on Pf. Whole-sporozoite (WSp) vaccination, targeting pre-erythrocytic (PE) parasite stages, is a promising strategy for immunization against malaria and several PfWSp-based vaccine candidates are currently undergoing clinical evaluation. In contrast, no WSp candidates have been developed for Pv, mainly due to constraints in the production of Pv sporozoites in the laboratory. Recently, we developed a novel approach for WSp vaccination against Pf based on the use of transgenic rodent P. berghei (Pb) sporozoites expressing immunogens of this human-infective parasite. We showed that this platform can be used to deliver PE Pf antigens, eliciting both targeted humoral responses and cross-species cellular immune responses against Pf. Here we explored this WSp platform for the delivery of Pv antigens. As the Pv circumsporozoite protein (CSP) is a leading vaccine candidate antigen, we generated a transgenic Pb parasite, PbviVac, that, in addition to its endogenous PbCSP, expresses PvCSP under the control of a strictly PE promoter. Immunofluorescence microscopy analyses confirmed that both the PbCSP and the PvCSP antigens are expressed in PbviVac sporozoites and liver stages and that PbviVac sporozoite infectivity of hepatic cells is similar to that of its wild-type Pb counterpart. Immunization of mice with PbviVac sporozoites elicits the production of anti-PvCSP antibodies that efficiently recognize and bind to Pv sporozoites. Our results warrant further development and evaluation of PbviVac as a surrogate for WSp vaccination against Pv malaria.

2.
Chem Commun (Camb) ; 56(96): 15137-15140, 2020 Dec 08.
Article in English | MEDLINE | ID: mdl-33211039

ABSTRACT

The molecular basis of antibody 5E5, which recognizes the entire GalNAc unit as a primary epitope is disclosed. The antibody's contacts with the peptide are mostly limited to two residues, allowing it to show some degree of promiscuity. These findings open the door to the chemical design of peptide-mimetics for developing efficient anti-cancer vaccines and diagnostic tools.


Subject(s)
Antibodies, Monoclonal/chemistry , Antineoplastic Agents/chemistry , Cancer Vaccines/chemistry , Lectins/chemistry , Mucin-1/chemistry , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Cancer Vaccines/pharmacology , Drug Screening Assays, Antitumor , Glycopeptides/chemistry , Glycosylation , Humans , Hydrogen Bonding , Lectins/pharmacology , Molecular Dynamics Simulation , Peptide Fragments/chemistry , Protein Conformation , Structure-Activity Relationship
3.
RSC Chem Biol ; 1(4): 251-262, 2020 Oct 01.
Article in English | MEDLINE | ID: mdl-34458764

ABSTRACT

The bone marrow tyrosine kinase in chromosome X (BMX) is pursued as a drug target because of its role in various pathophysiological processes. We designed BMX covalent inhibitors with single-digit nanomolar potency with unexploited topological pharmacophore patterns. Importantly, we reveal the first X-ray crystal structure of covalently inhibited BMX at Cys496, which displays key interactions with Lys445, responsible for hampering ATP catalysis and the DFG-out-like motif, typical of an inactive conformation. Molecular dynamic simulations also showed this interaction for two ligand/BMX complexes. Kinome selectivity profiling showed that the most potent compound is the strongest binder, displays intracellular target engagement in BMX-transfected cells with two-digit nanomolar inhibitory potency, and leads to BMX degradation PC3 in cells. The new inhibitors displayed anti-proliferative effects in androgen-receptor positive prostate cancer cells that where further increased when combined with known inhibitors of related signaling pathways, such as PI3K, AKT and Androgen Receptor. We expect these findings to guide development of new selective BMX therapeutic approaches.

4.
Biochemistry ; 58(26): 2861-2866, 2019 07 02.
Article in English | MEDLINE | ID: mdl-31243992

ABSTRACT

The recent discovery of the osmosensitive calcium (Ca2+) channel OSCA has revealed the potential mechanism by which plant cells sense diverse stimuli. Osmosensory transporters and mechanosensitive channels can detect and respond to osmotic shifts that play an important role in active cell homeostasis. Members of the TMEM63 family of proteins are described as the closest homologues of OSCAs. Here, we characterize TMEM63B, a mammalian homologue of OSCAs, recently classified as mechanosensitive. In HEK293T cells, TMEM63B localizes to the plasma membrane and is associated with F-actin. This Ca2+-permeable channel specifically induces Ca2+ influx across the membrane in response to extracellular Ca2+ concentration and hyperosmolarity. In addition, overexpression of TMEM63B in HEK293T cells significantly enhanced cell migration and wound healing. The link between Ca2+ osmosensitivity and cell migration might help to establish TMEM63B's pathogenesis, for example, in cancer in which it is frequently overexpressed.


Subject(s)
Calcium Channels/metabolism , Calcium/metabolism , Cell Movement , Epithelial Cells/cytology , Actins/metabolism , Calcium Channels/analysis , Calcium Channels/genetics , Cell Membrane/metabolism , Epithelial Cells/metabolism , HEK293 Cells , Humans , Models, Molecular , Up-Regulation , Wound Healing
5.
ACS Chem Biol ; 13(11): 3153-3160, 2018 11 16.
Article in English | MEDLINE | ID: mdl-30278129

ABSTRACT

Immunotoxins are proteins containing a cell-targeting element linked to a toxin that are under investigation for next-generation cancer treatment. However, these agents are difficult to synthesize, chemically heterogeneous, expensive, and show toxicity toward healthy cells. In this work, we describe the synthesis and characterization of a new type of immunotoxin that showed exquisite selectivity toward targeted cells. In our construct, targeting molecules were covalently attached or genetically fused to oligomeric pore-forming toxins. The activity of the immunotoxin was then caged by fusing a soluble protein to the transmembrane domain and activated via cleavage with furin, which is a protease that is overexpressed in many cancer cells. During the several coupling steps, directed evolution allowed the efficient synthesis of the molecules in E. coli cells, as well as selection for further specificity toward targeted cells. The final construct showed no off-target activity, while acquiring an additional degree of specificity toward the targeted cells upon activation. The pore-forming toxins described here do not require internalization to operate, while the many protomeric subunits can be individually modified to refine target specificity.


Subject(s)
Cnidarian Venoms/pharmacology , Immunotoxins/pharmacology , Pore Forming Cytotoxic Proteins/pharmacology , Recombinant Fusion Proteins/pharmacology , Tetrahydrofolate Dehydrogenase/pharmacology , Animals , Cell Line, Tumor , Cell Membrane/metabolism , Cnidarian Venoms/genetics , Directed Molecular Evolution/methods , Drug Design , Escherichia coli/genetics , Escherichia coli/metabolism , Folic Acid/chemistry , Furin/metabolism , Humans , Immunotoxins/chemistry , Immunotoxins/genetics , Immunotoxins/metabolism , Mutagenesis , Pore Forming Cytotoxic Proteins/genetics , Proteolysis , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Salmonella typhi/chemistry , Sea Anemones/chemistry , Tetrahydrofolate Dehydrogenase/genetics , Tetrahydrofolate Dehydrogenase/metabolism
6.
Eur J Med Chem ; 149: 69-78, 2018 Apr 10.
Article in English | MEDLINE | ID: mdl-29499488

ABSTRACT

Hybrid compounds may play a critical role in the context of the malaria eradication agenda, which will benefit from therapeutic tools active against the symptomatic erythrocytic stage of Plasmodium infection, and also capable of eliminating liver stage parasites. To address the need for efficient multistage antiplasmodial compounds, a small library of 1,2,4,5-tetraoxane-8- aminoquinoline hybrids, with the metabolically labile C-5 position of the 8-aminoquinoline moiety blocked with aryl groups, was synthesized and screened for antiplasmodial activity and metabolic stability. The hybrid compounds inhibited development of intra-erythrocytic forms of the multidrug-resistant Plasmodium falciparum W2 strain, with EC50 values in the nM range, and with low cytotoxicity against mammalian cells. The compounds also inhibited the development of P. berghei liver stage parasites, with the most potent compounds displaying EC50 values in the low µM range. SAR analysis revealed that unbranched linkers between the endoperoxide and 8-aminoquinoline pharmacophores are most beneficial for dual antiplasmodial activity. Importantly, hybrids were significantly more potent than a 1:1 mixture of 8-aminoquinoline-tetraoxane, highlighting the superiority of the hybrid approach over the combination therapy. Furthermore, aryl substituents at C-5 of the 8-aminoquinoline moiety improve the compounds' metabolic stability when compared with their primaquine (i.e. C-5 unsubstituted) counterparts. Overall, this study reveals that blocking the quinoline C-5 position does not result in loss of dual-stage antimalarial activity, and that tetraoxane-8- aminoquinoline hybrids are an attractive approach to achieve elimination of exo- and intraerythrocytic parasites, thus with the potential to be used in malaria eradication campaigns.


Subject(s)
Aminoquinolines/chemistry , Aminoquinolines/therapeutic use , Antimalarials/chemical synthesis , Aminoquinolines/metabolism , Animals , Antimalarials/metabolism , Antimalarials/pharmacology , Drug Evaluation, Preclinical , Drug Stability , Erythrocytes/parasitology , Humans , Liver/parasitology , Peroxides/chemistry , Peroxides/metabolism , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Small Molecule Libraries/chemical synthesis , Structure-Activity Relationship
7.
J Am Chem Soc ; 139(50): 18255-18261, 2017 12 20.
Article in English | MEDLINE | ID: mdl-29166012

ABSTRACT

A structure-based design of a new generation of tumor-associated glycopeptides with improved affinity against two anti-MUC1 antibodies is described. These unique antigens feature a fluorinated proline residue, such as a (4S)-4-fluoro-l-proline or 4,4-difluoro-l-proline, at the most immunogenic domain. Binding assays using biolayer interferometry reveal 3-fold to 10-fold affinity improvement with respect to the natural (glyco)peptides. According to X-ray crystallography and MD simulations, the fluorinated residues stabilize the antigen-antibody complex by enhancing key CH/π interactions. Interestingly, a notable improvement in detection of cancer-associated anti-MUC1 antibodies from serum of patients with prostate cancer is achieved with the non-natural antigens, which proves that these derivatives can be considered better diagnostic tools than the natural antigen for prostate cancer.


Subject(s)
Antibodies/chemistry , Drug Design , Mucin-1/chemistry , Proline/analogs & derivatives , Amino Acid Sequence , Antibodies/blood , Binding Sites, Antibody , Crystallography, X-Ray , Humans , Molecular Dynamics Simulation , Mucin-1/genetics , Peptides/chemistry , Peptides/genetics , Proline/chemistry
8.
Chemistry ; 23(64): 16219-16230, 2017 Nov 16.
Article in English | MEDLINE | ID: mdl-28763123

ABSTRACT

Mercury pollution threatens the environment and human health across the globe. This neurotoxic substance is encountered in artisanal gold mining, coal combustion, oil and gas refining, waste incineration, chloralkali plant operation, metallurgy, and areas of agriculture in which mercury-rich fungicides are used. Thousands of tonnes of mercury are emitted annually through these activities. With the Minamata Convention on Mercury entering force this year, increasing regulation of mercury pollution is imminent. It is therefore critical to provide inexpensive and scalable mercury sorbents. The research herein addresses this need by introducing low-cost mercury sorbents made solely from sulfur and unsaturated cooking oils. A porous version of the polymer was prepared by simply synthesising the polymer in the presence of a sodium chloride porogen. The resulting material is a rubber that captures liquid mercury metal, mercury vapour, inorganic mercury bound to organic matter, and highly toxic alkylmercury compounds. Mercury removal from air, water and soil was demonstrated. Because sulfur is a by-product of petroleum refining and spent cooking oils from the food industry are suitable starting materials, these mercury-capturing polymers can be synthesised entirely from waste and supplied on multi-kilogram scales. This study is therefore an advance in waste valorisation and environmental chemistry.


Subject(s)
Mercury/chemistry , Plant Oils/chemistry , Sulfur/chemistry , Adsorption , Air Pollutants/chemistry , Calorimetry, Differential Scanning , Polymers/chemical synthesis , Polymers/chemistry , Recycling , Soil Pollutants/chemistry , Surface Properties , Thermogravimetry , Water Pollutants, Chemical/chemistry
9.
Angew Chem Int Ed Engl ; 56(1): 243-247, 2017 01 02.
Article in English | MEDLINE | ID: mdl-27930843

ABSTRACT

The cleavage of a protecting group from a protein or drug under bioorthogonal conditions enables accurate spatiotemporal control over protein or drug activity. Disclosed herein is that vinyl ethers serve as protecting groups for alcohol-containing molecules and as reagents for bioorthogonal bond-cleavage reactions. A vinyl ether moiety was installed in a range of molecules, including amino acids, a monosaccharide, a fluorophore, and an analogue of the cytotoxic drug duocarmycin. Tetrazine-mediated decaging proceeded under biocompatible conditions with good yields and reasonable kinetics. Importantly, the nontoxic, vinyl ether duocarmycin double prodrug was successfully decaged in live cells to reinstate cytotoxicity. This bioorthogonal reaction presents broad applicability and may be suitable for in vivo applications.


Subject(s)
Alcohols/metabolism , Tetrazoles/metabolism , Vinyl Compounds/metabolism , Alcohols/chemistry , Cell Line, Tumor , Cycloaddition Reaction , Electrons , Hep G2 Cells , Humans , Kinetics , Molecular Structure , Quantum Theory , Tetrazoles/chemistry , Vinyl Compounds/chemistry
10.
Article in English | MEDLINE | ID: mdl-27895022

ABSTRACT

Avermectins are powerful endectocides with an established potential to reduce the incidence of vector-borne diseases. Here, we show that several avermectins inhibit the hepatic stage of Plasmodium infection in vitro Notably, ivermectin potently inhibits liver infection in vivo by impairing parasite development inside hepatocytes. This impairment has a clear impact on the ensuing blood stage parasitemia, reducing disease severity and enhancing host survival. Ivermectin has been proposed as a tool to control malaria transmission because of its effects on the mosquito vector. Our study extends the effect of ivermectin to the early stages of mammalian host infection and supports the inclusion of this multipurpose drug in malaria control strategies.


Subject(s)
Ivermectin/analogs & derivatives , Ivermectin/therapeutic use , Liver/parasitology , Malaria/drug therapy , Plasmodium/drug effects , Plasmodium/pathogenicity , Animals , Cell Line, Tumor , Culicidae , Humans
11.
Nat Commun ; 7: 13128, 2016 10 26.
Article in English | MEDLINE | ID: mdl-27782215

ABSTRACT

Maleimides remain the reagents of choice for the preparation of therapeutic and imaging protein conjugates despite the known instability of the resulting products that undergo thiol-exchange reactions in vivo. Here we present the rational design of carbonylacrylic reagents for chemoselective cysteine bioconjugation. These reagents undergo rapid thiol Michael-addition under biocompatible conditions in stoichiometric amounts. When using carbonylacrylic reagents equipped with PEG or fluorophore moieties, this method enables access to protein and antibody conjugates precisely modified at pre-determined sites. Importantly, the conjugates formed are resistant to degradation in plasma and are biologically functional, as demonstrated by the selective imaging and detection of apoptotic and HER2+ cells, respectively. The straightforward preparation, stoichiometric use and exquisite cysteine selectivity of the carbonylacrylic reagents combined with the stability of the products and the availability of biologically relevant cysteine-tagged proteins make this method suitable for the routine preparation of chemically defined conjugates for in vivo applications.


Subject(s)
Acrylates/chemistry , Benzoates/chemistry , Cysteine/chemistry , Immunoconjugates/chemistry , Staining and Labeling/methods , Sulfides/chemical synthesis , Acetonitriles/chemistry , Amino Acid Sequence , Annexin A5/chemistry , Cross-Linking Reagents/chemistry , HEK293 Cells , Humans , Maleimides/chemistry , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Stability , Receptor, ErbB-2/chemistry , Stereoisomerism , Trastuzumab/chemistry
12.
Sci Rep ; 6: 23218, 2016 Mar 17.
Article in English | MEDLINE | ID: mdl-26983695

ABSTRACT

Intense research efforts have been focused on the improvement of the efficiency and sensitivity of malaria diagnostics, especially in resource-limited settings for the detection of asymptomatic infections. Our recently developed magneto-optical (MO) method allows the accurate quantification of malaria pigment crystals (hemozoin) in blood by their magnetically induced rotation. First evaluations of the method using ß-hematin crystals and in vitro P. falciparum cultures implied its potential for high-sensitivity malaria diagnosis. To further investigate this potential, here we study the performance of the method in monitoring the in vivo onset and progression of the blood-stage infection in a rodent malaria model. Our results show that the MO method can detect the first generation of intraerythrocytic P. berghei parasites 66-76 hours after sporozoite injection, demonstrating similar sensitivity to Giesma-stained light microscopy and exceeding that of flow cytometric techniques. Magneto-optical measurements performed during and after the treatment of P. berghei infections revealed that both the follow up under treatment and the detection of later reinfections are feasible with this new technique. The present study demonstrates that the MO method - besides being label and reagent-free, automated and rapid - has a high in vivo sensitivity and is ready for in-field evaluation.


Subject(s)
Malaria/diagnosis , Microscopy/methods , Animals , Anopheles/parasitology , DNA, Protozoan/genetics , DNA, Protozoan/isolation & purification , DNA, Protozoan/metabolism , Disease Models, Animal , Female , Flow Cytometry/methods , Hemeproteins/genetics , Hemeproteins/metabolism , Life Cycle Stages , Malaria/parasitology , Malaria/veterinary , Mice , Mice, Inbred BALB C , Microscopy/instrumentation , Plasmodium berghei/growth & development , Plasmodium berghei/metabolism , Plasmodium berghei/pathogenicity , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , Real-Time Polymerase Chain Reaction
13.
J Med Chem ; 59(1): 264-81, 2016 Jan 14.
Article in English | MEDLINE | ID: mdl-26640981

ABSTRACT

The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 µM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 µM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 µM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.


Subject(s)
Aminoquinolines/chemical synthesis , Aminoquinolines/pharmacology , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Tetraoxanes/chemical synthesis , Tetraoxanes/pharmacology , Aminoquinolines/metabolism , Animals , Antimalarials/metabolism , Drug Evaluation, Preclinical , Ether-A-Go-Go Potassium Channels/drug effects , Hemin/antagonists & inhibitors , Hepatocytes/metabolism , Humans , In Vitro Techniques , Liver/parasitology , Mice , Microsomes, Liver/metabolism , Parasite Load , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Tetraoxanes/metabolism
14.
Angew Chem Int Ed Engl ; 55(5): 1714-8, 2016 Jan 26.
Article in English | MEDLINE | ID: mdl-26481099

ABSTRACT

A polysulfide material was synthesized by the direct reaction of sulfur and d-limonene, by-products of the petroleum and citrus industries, respectively. The resulting material was processed into functional coatings or molded into solid devices for the removal of palladium and mercury salts from water and soil. The binding of mercury(II) to the sulfur-limonene polysulfide resulted in a color change. These properties motivate application in next-generation environmental remediation and mercury sensing.


Subject(s)
Cyclohexenes/chemistry , Metals/isolation & purification , Soil Pollutants/isolation & purification , Sulfides/chemistry , Sulfur/chemistry , Terpenes/chemistry , Water Pollutants, Chemical/isolation & purification , Chromatography, Gel , Limonene , Microscopy, Electron, Scanning
15.
ChemMedChem ; 10(5): 883-90, 2015 May.
Article in English | MEDLINE | ID: mdl-25784585

ABSTRACT

A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P. berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials.


Subject(s)
Antimalarials/pharmacology , Erythrocytes/parasitology , Liver/parasitology , Malaria/drug therapy , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Triazines/pharmacology , Animals , Antimalarials/chemistry , CHO Cells , Cell Line, Tumor , Cell Proliferation , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Humans , Malaria/parasitology , Parasitic Sensitivity Tests , Rats , Structure-Activity Relationship , Triazines/chemistry
16.
Chem Commun (Camb) ; 51(19): 3993-6, 2015 Mar 07.
Article in English | MEDLINE | ID: mdl-25660271

ABSTRACT

We report the design and synthesis of an aquacarbonyl Ru(II) dication cis-[Ru(CO)2(H2O)4](2+) reagent for histidine (His)-selective metallation of interleukin (IL)-8 at site 33. The artificial, non-toxic interleukin (IL)-8-Ru(II)(CO)2 metalloprotein retained IL-8-dependent neutrophil chemotactic activity and was shown to spontaneously release CO in live cells.


Subject(s)
Biomimetic Materials/chemistry , Histidine/chemistry , Metalloproteins/chemistry , Ruthenium/chemistry , Chemotaxis , HeLa Cells , Humans , Interleukin-8/chemistry , Neutrophils/cytology
17.
Infect Immun ; 83(3): 1172-80, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25583524

ABSTRACT

Following transmission through a mosquito bite to the mammalian host, Plasmodium parasites first invade and replicate inside hepatocytes before infecting erythrocytes and causing malaria. The mechanisms limiting Plasmodium reinfections in humans living in regions of malaria endemicity have mainly been explored by studying the resistance induced by the blood stage of infection. However, epidemiologic studies have suggested that in high-transmission areas, preerythrocytic stages also activate host resistance to reinfection. This, along with the recent discovery that liver infections trigger a specific and effective type I interferon (IFN) response, prompted us to hypothesize that this pre-erythrocyte-stage-induced resistance is linked to liver innate immunity. Here, we combined experimental approaches and mathematical modeling to recapitulate field studies and understand the molecular basis behind such resistance. We present a newly established mouse reinfection model and demonstrate that rodent malaria liver-stage infection inhibits reinfection. This protection relies on the activation of innate immunity and involves the type I IFN response and the antimicrobial cytokine gamma IFN (IFN-γ). Importantly, mathematical simulations indicate that the predictions based on our experimental murine reinfection model fit available epidemiological data. Overall, our study revealed that liver-stage-induced innate immunity may contribute to the preerythrocytic resistance observed in humans in regions of malaria hyperendemicity.


Subject(s)
Adaptive Immunity , Liver/immunology , Malaria/immunology , Models, Statistical , Plasmodium berghei/immunology , Sporozoites/immunology , Adaptor Proteins, Signal Transducing , Animals , Anopheles/parasitology , Carrier Proteins/genetics , Carrier Proteins/immunology , Gene Expression Regulation/immunology , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Immunity, Innate , Immunologic Memory , Interferon Regulatory Factor-7/genetics , Interferon Regulatory Factor-7/immunology , Interferon-gamma/deficiency , Interferon-gamma/genetics , Interferon-gamma/immunology , Intracellular Signaling Peptides and Proteins , Liver/parasitology , Malaria/genetics , Malaria/parasitology , Mice , Mice, Inbred C57BL , Mice, Knockout , Parasite Load , Plasmodium berghei/growth & development , Proteins/genetics , Proteins/immunology , RNA-Binding Proteins , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/immunology , Sporozoites/growth & development , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/immunology
18.
Chem Commun (Camb) ; 51(25): 5250-2, 2015 Mar 28.
Article in English | MEDLINE | ID: mdl-25415185

ABSTRACT

We have developed a strategy for selective imaging of collagen in live foetal ovine osteoblasts. Our approach involves the incorporation of an azide-tagged proline in the biosynthesis of collagen followed by labelling using a strain-promoted [3+2] azide-alkyne cycloaddition reaction.


Subject(s)
Azides/chemistry , Collagen/analysis , Osteoblasts/chemistry , Osteoblasts/cytology , Proline/chemistry , Alkynes/chemistry , Cell Survival , Cells, Cultured , Cyclization , Humans
19.
Angew Chem Int Ed Engl ; 54(4): 1172-5, 2015 Jan 19.
Article in English | MEDLINE | ID: mdl-25477186

ABSTRACT

We demonstrate that Ru(II)(CO)2-protein complexes, formed by the reaction of the hydrolytic decomposition products of [fac-RuCl(κ(2)-H2NCH2CO2)(CO)3] (CORM-3) with histidine residues exposed on the surface of proteins, spontaneously release CO in aqueous solution, cells, and mice. CO release was detected by mass spectrometry (MS) and confocal microscopy using a CO-responsive turn-on fluorescent probe. These findings support our hypothesis that plasma proteins act as CO carriers after in vivo administration of CORM-3. CO released from a synthetic bovine serum albumin (BSA)-Ru(II)(CO)2 complex leads to downregulation of the cytokines interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α in cancer cells. Finally, administration of BSA-Ru(II)(CO)2 in mice bearing a colon carcinoma tumor results in enhanced CO accumulation at the tumor. Our data suggest the use of Ru(II)(CO)2-protein complexes as viable alternatives for the safe and spatially controlled delivery of therapeutic CO in vivo.


Subject(s)
Organometallic Compounds/chemistry , Serum Albumin, Bovine/chemistry , Animals , Carbon Monoxide/analysis , Carbon Monoxide/metabolism , Cattle , Cell Line, Tumor , Female , HeLa Cells , Histidine/chemistry , Humans , Interleukin-10/metabolism , Interleukin-6/metabolism , Mass Spectrometry , Mice , Mice, Inbred BALB C , Neoplasms/drug therapy , Prodrugs/chemistry , Prodrugs/metabolism , Prodrugs/therapeutic use , Serum Albumin, Bovine/metabolism , Tissue Distribution , Transplantation, Heterologous , Tumor Necrosis Factor-alpha/metabolism
20.
ACS Med Chem Lett ; 5(2): 108-12, 2014 Feb 13.
Article in English | MEDLINE | ID: mdl-24900781

ABSTRACT

In a search for effective compounds against both the blood- and liver-stages of infection by malaria parasites with the ability to block the transmission of the disease to mosquito vectors, a series of hybrid compounds combining either a 1,2,4-trioxane or 1,2,4,5-tetraoxane and 8-aminoquinoline moieties were synthesized and screened for their antimalarial activity. These hybrid compounds showed high potency against both exoerythrocytic and erythrocytic forms of malaria parasites, comparable to representative trioxane-based counterparts. Furthermore, they efficiently blocked the development of the sporogonic cycle in the mosquito vector. The tetraoxane-based hybrid 5, containing an amide linker between the two moieties, effectively cleared a patent blood-stage P. berghei infection in mice after i.p. administration. Overall, these results indicate that peroxide-8-aminoquinoline hybrids are excellent starting points to develop an agent that conveys all the desired antimalarial multistage activities in a single chemical entity and, as such, with the potential to be used in malaria elimination campaigns.

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