scholarly journals Glideosomal GAP50 binders that inhibit invasion and restrict malaria parasite in vitro and in vivo

2021 ◽  
Author(s):  
Prakhar Agrawal ◽  
Surekha Kumari ◽  
Upendra Sharma ◽  
Dinkar Sahal
Keyword(s):  
Mouse Model ◽  
Small Molecules ◽  
Malaria Parasite ◽  
Drug Combinations ◽  
Antiplasmodial Activity ◽  
Modern World ◽  
Anchor Protein

Abstract Malaria continues to be a killer disease even in the modern world. Vaccines and drugs have a lot to learn from the malaria parasite before they can be successful. Here, using a filter for glideosomal anchor protein PfGAP50, we have explored a plethora of small molecules to shortlist eight GAP50 binders with promising antiplasmodial activity (IC50 < 3 µM) that are also highly selective. Of these, Hayatinin, Bedaquiline, MMV688271, Curine, and Brilacidin with PfINDO IC50 ≤ 1 µM were found to stall merozoites invasion by inhibiting IMC formation besides increasing ROS levels in trophozoites. Bedaquiline loaded healthy RBCs showed prophylactic ability to prevent intraerythrocytic development of malaria parasite. Synergistic activities with ΣFIC values as low as 0.22 (Curine and Artemisinin) or 0.37 (Bedaquiline and Artemisinin) augur well for the development of drug combinations to combat malaria effectively. Interestingly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia in the mouse model of malaria.

scholarly journals Glideosomal GAP50 binders that inhibit invasion and restrict malaria parasite in vitro and in vivo

2021 ◽  
Author(s):  
PRAKHAR AGRAWAL ◽  
SUREKHA KUMARI ◽  
UPENDRA SHARMA ◽  
DINKAR SAHAL
Keyword(s):  
Mouse Model ◽  
Small Molecules ◽  
Malaria Parasite ◽  
Drug Combinations ◽  
Antiplasmodial Activity ◽  
Modern World ◽  
Anchor Protein

Abstract Malaria continues to be a killer disease even in the modern world. Vaccines and drugs have a lot to learn from the malaria parasite before they can be successful. Here, using a filter for glideosomal anchor protein PfGAP50, we have explored a plethora of small molecules to shortlist eight GAP50 binders with promising antiplasmodial activity (IC50 < 3 µM) that are also highly selective. Of these, Hayatinin, Bedaquiline, MMV688271, Curine, and Brilacidin with PfINDO IC50 ≤ 1 µM were found to stall merozoites invasion by inhibiting IMC formation besides increasing ROS levels in trophozoites. Bedaquiline loaded healthy RBCs showed prophylactic ability to prevent intraerythrocytic development of malaria parasite. Synergistic activities with ΣFIC values as low as 0.22 (Curine and Artemisinin) or 0.37 (Bedaquiline and Artemisinin) augur well for the development of drug combinations to combat malaria effectively. Interestingly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia in the mouse model of malaria.

scholarly journals Antiplasmodial and Cytotoxic Cytochalasins from an Endophytic Fungus, Nemania sp. UM10M, Isolated from a Diseased Torreya taxifolia Leaf

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 777 ◽  
Author(s):  
Mallika Kumarihamy ◽  
Daneel Ferreira ◽  
Edward Croom ◽  
Rajnish Sahu ◽  
Babu Tekwani ◽  
...  
Keyword(s):  
Mouse Model ◽  
Solid Tumor ◽  
Endophytic Fungus ◽  
Antimalarial Activity ◽  
Vero Cells ◽  
Antiplasmodial Activity ◽  
Etoac Extract ◽  
Bioassay Guided Fractionation

Bioassay-guided fractionation of an EtOAc extract of the broth of the endophytic fungus Nemania sp. UM10M (Xylariaceae) isolated from a diseased Torreya taxifolia leaf afforded three known cytochalasins, 19,20-epoxycytochalasins C (1) and D (2), and 18-deoxy-19,20-epoxy-cytochalasin C (3). All three compounds showed potent in vitro antiplasmodial activity and phytotoxicity with no cytotoxicity to Vero cells. These compounds exhibited moderate to weak cytotoxicity to some of the cell lines of a panel of solid tumor (SK-MEL, KB, BT-549, and SK-OV-3) and kidney epithelial cells (LLC-PK11). Evaluation of in vivo antimalarial activity of 19,20-epoxycytochalasin C (1) in a mouse model at 100 mg/kg dose showed that this compound had weak suppressive antiplasmodial activity and was toxic to animals.

scholarly journals Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine and Linezolid in a Murine Model of Tuberculosis.

2021 ◽  
Author(s):  
Yu Wei ◽  
Buhari Yusuf ◽  
Wang Shuai ◽  
Tian Xirong ◽  
H. M. Adnan Hameed ◽  
...  
Keyword(s):  
Mouse Model ◽  
Murine Model ◽  
Drug Combinations ◽  
Bacterial Burden ◽  
Injectable Drug ◽  
Drug Candidates ◽  
Stopping Treatment ◽  
Fast Acting

Toxicity and inconvenience associated with the use of injectable drug-containing regimens for tuberculosis (TB) have made all-oral regimens a preferred alternative. Widespread resistance to fluoroquinolones and pyrazinamide makes it essential to identify new drug candidates and study their effects on current regimens for TB. TB47 is a pyrazolo[1,5-a]pyridine-3-carboxamide with powerful synergistic in vitro and in vivo activities against mycobacteria, especially with clofazimine. Here, we investigated the bactericidal and sterilizing activities of novel oral regimens containing TB47 + clofazimine + linezolid, and the potential roles of levofloxacin and/or pyrazinamide in such drug combinations. Using a well-established mouse model, we assessed the effect of these regimens on bacterial burden in the lung during treatment and relapse (4 months after stopping treatment + immunosuppression). Our findings indicate that the TB47 + clofazimine + linezolid + pyrazinamide, with/without levofloxacin, regimens had fast-acting (4 months) sterilizing activity and no relapse was observed. When pyrazinamide was excluded from the regimen, treatment times were longer (5-6 months) to achieve sterilizing conditions. We propose that TB47 + clofazimine + linezolid can form a highly sterilizing block for use as an alternative pan-TB regimen.

scholarly journals Antiplasmodial Potential of Indonesian Medicinal Plants

2020 ◽  
Author(s):  
Nurhayati Bialangi ◽  
Mohamad Adam Mustapa ◽  
Yuszda K Salimi ◽  
Weny J.A Musa ◽  
Ari Widiyantoro ◽  
...  
Keyword(s):  
Medicinal Plants ◽  
Mouse Model ◽  
Traditional Medicine ◽  
Post Infection ◽  
High Ratio ◽  
Antiplasmodial Activity ◽  
Dependent Manner ◽  
Dose Dependent

Abstract Background: Species A. paniculata (Burm. f.) Nees known as″ Sambiloto ″ and P. pellucida L. Kunth known as″ Suruhan ″ are mainly distributed in Indonesia and their combination was used as a traditional medicine for treating malaria diseases. However, no information appears to have evaluated the antiplasmodial potential of the two plants. This research aimed to evaluate the antiplasmodial activity of the two plants and the species P. pellucida L. Kunth alone as a source of antiplasmodial agent. Methods: In vitro test of the AP-PP and PP extracts against Pf D-10 (chloroquine-sensitive) were performed as described by Desjardins et al. An in vivo test of the PP extract in mice infected with Pb ANKA was performed using Peters´ 4-day suppressive test. Parasitemia, growth and inhibition rates were determined via Giemsa-stained smear of blood and analyzed microscopically. Survival was followed up until day 21 post-infection.Results: The increased ratio of the PP extract (20:80) exhibited significant antiplasmodial in contrast to the high ratio of the AP extract (IC50, 62.01 mg/mL). Further evaluation of the PP extract alone displayed better antiplasmodial activity with an IC50 value of 4.0 mg/mL. Furthermore, an in vivo test of the PP extract in BALB/c albino mice infected with Pb ANKA exhibited a significant chemosuppressive effect in a dose-dependent manner.Conclusion: The increased ratio of the PP extract exhibited a major contribution for their activity. The PP extract alone showed better antiplasmodial activity than the AP extract and their combination. An in vivo test confirmed the efficacy of the PP extract in mouse model.

Conjugates of Classical DNA/RNA Binder with Nucleobase: Chemical, Biochemical and Biomedical Applications

2019 ◽  
Vol 26 (30) ◽  
pp. 5609-5624
Author(s):  
Dijana Saftić ◽  
Željka Ban ◽  
Josipa Matić ◽  
Lidija-Marija Tumirv ◽  
Ivo Piantanida
Keyword(s):  
Molecular Weight ◽  
Small Molecules ◽  
Biomedical Applications ◽  
Protein Targets ◽  
New Class ◽  
Rna Targets ◽  
Covalently Linked ◽  
Structural Aspects

: Among the most intensively studied classes of small molecules (molecular weight < 650) in biomedical research are small molecules that non-covalently bind to DNA/RNA, and another intensively studied class is nucleobase derivatives. Both classes have been intensively elaborated in many books and reviews. However, conjugates consisting of DNA/RNA binder covalently linked to nucleobase are much less studied and have not been reviewed in the last two decades. Therefore, this review summarized reports on the design of classical DNA/RNA binder – nucleobase conjugates, as well as data about their interactions with various DNA or RNA targets, and even in some cases protein targets are involved. According to these data, the most important structural aspects of selective or even specific recognition between small molecule and target are proposed, and where possible related biochemical and biomedical aspects were discussed. The general conclusion is that this, rather new class of molecules showed an amazing set of recognition tools for numerous DNA or RNA targets in the last two decades, as well as few intriguing in vitro and in vivo selectivities. Several lead research lines show promising advancements toward either novel, highly selective markers or bioactive, potentially druggable molecules.

scholarly journals A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuejie Gao ◽  
Bo Li ◽  
Anqi Ye ◽  
Houcai Wang ◽  
Yongsheng Xie ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Burden ◽  
High Rate ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Xenograft Mouse Model

Abstract Background Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. Methods We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. Results The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. Conclusion The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.

In vitro and in vivo antiplasmodial activity of novel quinoline derivative compounds by molecular hybridization

2021 ◽  
Vol 215 ◽  
pp. 113271
Author(s):  
Juliane Aparecida Marinho ◽  
Daniel Silqueira Martins Guimarães ◽  
Nícolas Glanzmann ◽  
Giovana de Almeida Pimentel ◽  
Izabelle Karine da Costa Nunes ◽  
...  
Keyword(s):  
Quinoline Derivative ◽  
Antiplasmodial Activity ◽  
Molecular Hybridization

scholarly journals MODL-12. DEVELOPMENT OF A NOVEL IMMUNOCOMPETENT MOUSE MODEL FOR DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii413-iii413
Author(s):  
Maggie Seblani ◽  
Markella Zannikou ◽  
Katarzyna Pituch ◽  
Liliana Ilut ◽  
Oren Becher ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Mouse Model ◽  
Growth Factor Receptor ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Time Of Application ◽  
Tumor Associated Antigen ◽  
Sarcoma Virus

Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor affecting young children. Immunotherapies hold promise however the lack of immunocompetent models recreating a faithful tumor microenvironment (TME) remains a challenge for development of targeted immunotherapeutics. We propose to generate an immunocompetent DIPG mouse model through induced overexpression of interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-associated antigen overexpressed by glioma cells. A model with an intact TME permits comprehensive preclinical assessment of IL13Rα2-targeted immunotherapeutics. Our novel model uses the retroviral avian leucosis and sarcoma virus (RCAS) for in vivo gene delivery leading to IL13Rα2 expression in proliferating progenitor cells. Transfected cells expressing IL13Rα2 and PDGFB, a ligand for platelet derived growth factor receptor, alongside induced p53 loss via the Cre-Lox system are injected in the fourth ventricle in postnatal pups. We validated the expression of PDGFB and IL13Rα2 transgenes in vitro and in vivo and will characterize the TME through evaluation of the peripheral and tumor immunologic compartments using immunohistochemistry and flow cytometry. We confirmed expression of transgenes via flow cytometry and western blotting. Comparison of survival dynamics in mice inoculated with PDGFB alone with PDGFB+IL13Rα2 demonstrated that co-expression of IL13Rα2 did not significantly affect mice survival compared to the PDGFB model. At time of application, we initiated experiments to characterize the TME. Preliminary data demonstrate establishment of tumors within and adjacent to the brainstem and expression of target transgenes. Preclinical findings in a model recapitulating the TME may provide better insight into outcomes upon translation to clinical application.

scholarly journals TMOD-24. GENERATION AND CHARACTERIZATION OF A NOVEL TRANSGENIC IDO REPORTER MOUSE FOR IDO POSTTRANSLATIONAL MODIFICATION ANALYSIS IN SITU

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii233-ii233
Author(s):  
April Bell ◽  
Lijie Zhai ◽  
Erik Ladomersky ◽  
Kristen Lauing ◽  
Lakshmi Bollu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Cell ◽  
Central Nervous System Tumor ◽  
Post Translational Modifications ◽  
Reporter Mouse ◽  
C Terminus ◽  
Human Gbm

Abstract Glioblastoma (GBM) is the most common and aggressive primary central nervous system tumor in adults with a median survival of 14.6 months. GBM is a potently immunosuppressive cancer due in-part to the prolific expression of immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO). Tumor cell IDO facilitates the intratumoral accumulation of regulatory T cells (Tregs; CD4+CD25+FoxP3+). Although immunosuppressive IDO activity is canonically characterized by the conversion of tryptophan into kynurenine, we have utilized transgenic and syngeneic mouse models and mutant glioma lines to demonstrate that tumor cell IDO increases Treg accumulation independent of tryptophan metabolism. Here, we address the gap in our understanding of IDO signaling activity in vivo. Subcutaneously-engrafted human GBM expressing human IDO-GFP cDNA was isolated from immunodeficient humanized NSG-SGM3 mice. The tumor was immunoprecipitated for the GFP tag using GFP-TRAP followed by mass spectrometry which revealed a novel methylation site on a lysine residue at amino acid 373 in the IDO C-terminus region. Western blot analysis of IDO protein also revealed the presence of tyrosine phosphorylation. Additionally, we recently created a new transgenic IDO reporter mouse model whereby endogenous IDO is fused to GFP via a T2A linker (IDO→GFP). This model allows for the isolation of IDO+ cells in real-time and without causing cell death, thereby creating the opportunity for downstream molecular analysis of in situ-isolated GFP+ cells. Collectively, our work suggests that IDO non-enzyme activity may involve the post-translational modifications we recently identified. As IDO activity may differ between in vitro and in vivo modeling systems, we will use the new IDO→GFP reporter mouse model for an improved mechanistic understanding of how immunosuppressive IDO facilitates Treg accumulation in vivo.

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