Plasmodium falciparum purine nucleoside phosphorylase as a model in the search for new inhibitors by high throughput screening

Holanda, Rudson J.; Deves, Candida; Moreira-Dill, Leandro S.; Guimarães, César L.S.; Marttinelli, Leonardo K.B.; Fernandes, Carla Freire Celedônio; Medeiros, Patrícia S.M.; Pereira, Soraya dos Santos; Honda, Eduardo Rezende; Stábeli, Rodrigo G.; Santos, Daniel Silas Veras dos; Soares, Andreimar Martins; Silva, Luiz H. Pereira da

doi:10.1016/j.ijbiomac.2020.10.062

Cited by 4 publications

(2 citation statements)

References 47 publications

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“…Here, we presented surface plasmon resonance (SPR) as a first step in the search of new compounds that interact with falcipain 2 specifically. SPR allows for fast analysis of interacting ability between the macromolecule and the analyte, thereby permitting the determination of association and dissociation constants important for the selection of the inhibitor or binder ( Holanda et al, 2020 ). Here, we determined the binding affinity of FP2 and FP3 with NT23, ST72, and NT18 and studied the protein–drug interaction using surface plasmon resonance (SPR).…”

Section: Resultsmentioning

confidence: 99%

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

et al. 2022

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We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affinity and specificity toward FP2 were selected. Furthermore, the enzyme inhibition and surface plasmon resonance assays were performed which resulted in a compound ZINC12900664 (ST72) with potent inhibitory effects on purified FP2. ST72 exhibited strong growth inhibition of chloroquine-sensitive (3D7; EC50 = 2.8 µM) and chloroquine-resistant (RKL-9; EC50 = 6.7 µM) strains of Plasmodium falciparum. Stage-specific inhibition assays revealed a delayed and growth defect during parasite growth and development in parasites treated with ST72. Furthermore, ST72 significantly reduced parasite load and increased host survival in a murine model infected with Plasmodium berghei ANKA. No Evans blue staining in ST72 treatment indicated that ST72 mediated protection of blood–brain barrier integrity in mice infected with P. berghei. ST72 did not show any significant hemolysis or cytotoxicity against human HepG2 cells suggesting a good safety profile. Importantly, ST72 with CQ resulted in improved growth inhibitory activity than individual drugs in both in vitro and in vivo studies.

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Section: Resultsmentioning

confidence: 99%

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

et al. 2022

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“…2.4.2.1, PNP) is a well-known drug target including cancer and immunodeficiency diseases (Pant et al 2021 ; Parker et al 2020 ). PNP can reversibly catalyze phosphorolysis of purine nucleosides to form glycosidic bonds (Holanda et al 2020 ; Stachelska-Wierzchowska and Wierzchowski 2020 ; Timofeev et al 2020 ). Therefore, PNP is a significant catalyst in the metabolic pathway of purines and nucleosides, especially 2-fluoroadenosine and 2-fluorocordycepin (Kayushin et al 2021 ).…”

Section: Enzymatic Synthesis Of Fluorinated Compoundsmentioning

confidence: 99%

Enzymatic synthesis of fluorinated compounds

Cheng

2021

Appl Microbiol Biotechnol

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Fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. Fluorinated natural products in nature are rare, and the introduction of fluorine atoms into organic compound molecules can give these compounds new functions and make them have better performance. Therefore, the synthesis of fluorides has attracted more and more attention from biologists and chemists. Even so, achieving selective fluorination is still a huge challenge under mild conditions. In this review, the research progress of enzymatic synthesis of fluorinated compounds is summarized since 2015, including cytochrome P450 enzymes, aldolases, fluoroacetyl coenzyme A thioesterases, lipases, transaminases, reductive aminases, purine nucleoside phosphorylases, polyketide synthases, fluoroacetate dehalogenases, tyrosine phenol-lyases, glycosidases, fluorinases, and multienzyme system. Of all enzyme-catalyzed synthesis methods, the direct formation of the C-F bond by fluorinase is the most effective and promising method. The structure and catalytic mechanism of fluorinase are introduced to understand fluorobiochemistry. Furthermore, the distribution, applications, and future development trends of fluorinated compounds are also outlined. Hopefully, this review will help researchers to understand the significance of enzymatic methods for the synthesis of fluorinated compounds and find or create excellent fluoride synthase in future research. Key points • Fluorinated compounds are distributed in plants and microorganisms, and are used in imaging, medicine, materials science . • Enzyme catalysis is essential for the synthesis of fluorinated compounds . • The loop structure of fluorinase is the key to forming the C-F bond . Supplementary Information The online version contains supplementary material available at 10.1007/s00253-021-11608-0.

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Development of a continuous assay for high throughput screening to identify inhibitors of the purine salvage pathway in Plasmodium falciparum

Grube¹,

Gill²,

Roy

2022

SLAS Discovery

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Plasmodium falciparum purine nucleoside phosphorylase as a model in the search for new inhibitors by high throughput screening

Cited by 4 publications

References 47 publications

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

Enzymatic synthesis of fluorinated compounds

Development of a continuous assay for high throughput screening to identify inhibitors of the purine salvage pathway in Plasmodium falciparum

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