scholarly journals Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome

2021 ◽  
Vol 118 (39) ◽  
pp. e2107213118
Author(s):  
Stanley C. Xie ◽  
Riley D. Metcalfe ◽  
Hirotake Mizutani ◽  
Tanya Puhalovich ◽  
Eric Hanssen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Proteasome Inhibitors ◽  
Human Cell Line ◽  
20S Proteasome ◽  
Binding Modes ◽  
Development Of Resistance ◽  
Amino Amide ◽  
Cancer Agent

The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax. They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.

scholarly journals Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽  
1990 ◽  
Vol 76 (6) ◽  
pp. 1250-1255 ◽  
Author(s):  
S Whitehead ◽  
TE Peto
Keyword(s):  
Plasmodium Falciparum ◽  
Growth Inhibition ◽  
Antimalarial Activity ◽  
Clinical Malaria ◽  
Inhibitory Effect ◽  
Parasite Development ◽  
And Control ◽  
Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

scholarly journals Antimalarial activity of betulinic acid and derivatives in vitro against Plasmodium falciparum and in vivo in P. berghei-infected mice

2009 ◽  
Vol 105 (1) ◽  
pp. 275-279 ◽  
Author(s):  
Matheus Santos de Sá ◽  
José Fernando Oliveira Costa ◽  
Antoniana Ursine Krettli ◽  
Mariano Gustavo Zalis ◽  
Gabriela Lemos de Azevedo Maia ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Betulinic Acid ◽  
Antimalarial Activity

scholarly journals Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Letícia Tiburcio Ferreira ◽  
Juliana Rodrigues ◽  
Gustavo Capatti Cassiano ◽  
Tatyana Almeida Tavella ◽  
Kaira Cristina Peralis Tomaz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
In Silico ◽  
Antimalarial Activity ◽  
Drug Repositioning ◽  
Dna Gyrase ◽  
Plasmodium Yoelii ◽  
Computer Assisted ◽  
Content Type

ABSTRACT Widespread resistance against antimalarial drugs thwarts current efforts for controlling the disease and urges the discovery of new effective treatments. Drug repositioning is increasingly becoming an attractive strategy since it can reduce costs, risks, and time-to-market. Herein, we have used this strategy to identify novel antimalarial hits. We used a comparative in silico chemogenomics approach to select Plasmodium falciparum and Plasmodium vivax proteins as potential drug targets and analyzed them using a computer-assisted drug repositioning pipeline to identify approved drugs with potential antimalarial activity. Among the seven drugs identified as promising antimalarial candidates, the anthracycline epirubicin was selected for further experimental validation. Epirubicin was shown to be potent in vitro against sensitive and multidrug-resistant P. falciparum strains and P. vivax field isolates in the nanomolar range, as well as being effective against an in vivo murine model of Plasmodium yoelii. Transmission-blocking activity was observed for epirubicin in vitro and in vivo. Finally, using yeast-based haploinsufficiency chemical genomic profiling, we aimed to get insights into the mechanism of action of epirubicin. Beyond the target predicted in silico (a DNA gyrase in the apicoplast), functional assays suggested a GlcNac-1-P-transferase (GPT) enzyme as a potential target. Docking calculations predicted the binding mode of epirubicin with DNA gyrase and GPT proteins. Epirubicin is originally an antitumoral agent and presents associated toxicity. However, its antiplasmodial activity against not only P. falciparum but also P. vivax in different stages of the parasite life cycle supports the use of this drug as a scaffold for hit-to-lead optimization in malaria drug discovery.

scholarly journals Antiplasmodial Quinones from the Rhizomes of Kniphofia Foliosa

2013 ◽  
Vol 8 (9) ◽  
pp. 1934578X1300800 ◽  
Author(s):  
Martha Induli ◽  
Meron Gebru ◽  
Negera Abdissa ◽  
Hosea Akala ◽  
Ingrid Wekesa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Methyl Ether ◽  
Spectroscopic Data ◽  
Antimalarial Activity ◽  
In Vivo Assay

Extracts of the rhizomes of Kniphofia foliosa exhibited antiplasmodial activities against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 values of 3–5 μg/mL. A phenyloxanthrone, named 10-acetonylknipholone cyclooxanthrone (1) and an anthraquinone-anthrone dimer, chryslandicin 10-methyl ether (2), were isolated from the rhizomes, along with known quinones, including the rare phenylanthraquinone dimers, joziknipholones A and B. The structures of these compounds were determined based on spectroscopic data. This is the second report on the occurrence of the dimeric phenylanthraquinones in nature. In an in vitro antiplasmodial assay of the isolated compounds, activity was observed for phenylanthraquinones, anthraquinone-anthrone dimers and dimeric phenylanthraquinones, with joziknipholone A being the most active. The new compound, 10-acetonylknipholone cyclooxanthrone, also showed anti-plasmodial activity. In an in vivo assay, knipholone anthrone displayed marginal antimalarial activity.

Antimalarial Activity of Phenazines from Lapachol, β-Lapachone and Its Derivatives Against Plasmodium falciparum in vitro and Plasmodium berghei in vivo.

ChemInform ◽  
2004 ◽  
Vol 35 (26) ◽  
Author(s):  
Valter F. de Andrade-Neto ◽  
Marilia O. F. Goulart ◽  
Jorge F. da Silva Filho ◽  
Matuzalem J. da Silva ◽  
Maria do Carmo F. R. Pinto ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Plasmodium Berghei ◽  
Antimalarial Activity

scholarly journals In VitroandIn VivoAntimalarial Activity ofFicus thonningiiBlume (Moraceae) andLophira alataBanks (Ochnaceae), Identified from the Ethnomedicine of the Nigerian Middle Belt

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
M. O. Falade ◽  
D. O. Akinboye ◽  
G. O. Gbotosho ◽  
E. O. Ajaiyeoba ◽  
T. C. Happi ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Human Cell Line ◽  
New Drugs ◽  
Leaf Extracts ◽  
Potential Source ◽  
Hexane Extracts ◽  
Ficus Thonningii ◽  
Multiresistant Strains

Drug resistance inPlasmodium falciparumrequires that new drugs must be developed. Plants are a potential source for drug discovery and development. Two plants that used to treat febrile illnesses in Nigeria were tested forin vitroandin vivoantimalarial activity and cytotoxicity in cancer cell lines. Methanol, hexane, and ethyl acetate leaf extracts ofFicus thonningiiandLophira alatawere active inin vitroassays againstP. falciparumNF54 (sensitive) and K1 (multiresistant) strains. Hexane extracts ofF. thonningiiandL. alatawere the most effective extracts inin vitroassays with IC50of2.7±1.6 μg/mL and2.5±0.3 μg/mL for NF54 and10.4±1.6 μg/mL and2.5±2.1 μg/mL for K1 strain. All extracts were nontoxic in cytotoxicity assays against KB human cell line with IC50of over 20 μg/mL, demonstrating selectivity againstP. falciparum.In vivoanalysis shows that hexane extracts of both plants reduced parasitaemia. At the maximum dose tested,L. alatahad a 74.4% reduction of parasitaemia whileF. thonningiihad a reduction of 84.5%, both extracts prolonged animal survival in mice infected withP. bergheiNK65 when compared with vehicle treated controls. The antiplasmodial activity observed justifies the use of both plants in treating febrile conditions.

Hybrid molecules with potential in vitro antiplasmodial and in vivo antimalarial activity against drug‐resistant Plasmodium falciparum

2019 ◽  
Vol 40 (3) ◽  
pp. 931-971 ◽  
Author(s):  
Lian‐Shun Feng ◽  
Zhi Xu ◽  
Le Chang ◽  
Chuan Li ◽  
Xiao‐Fei Yan ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Drug Resistant ◽  
Hybrid Molecules

scholarly journals Polymorphism in PfMRP1 (Plasmodium falciparum Multidrug Resistance Protein 1) Amino Acid 1466 Associated with Resistance to Sulfadoxine-Pyrimethamine Treatment

2009 ◽  
Vol 53 (6) ◽  
pp. 2553-2556 ◽  
Author(s):  
Sabina Dahlström ◽  
M. Isabel Veiga ◽  
Andreas Mårtensson ◽  
Anders Björkman ◽  
J. Pedro Gil
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Antimalarial Activity ◽  
Intermittent Preventive Treatment ◽  
Genetic Alterations ◽  
Multidrug Resistance Protein ◽  
Nucleotide Polymorphisms ◽  
Resistance Protein ◽  
Selection Of

ABSTRACT Sulfadoxine-pyrimethamine (SP) remains widely recommended for intermittent preventive treatment against Plasmodium falciparum malaria for pregnant women and infants in Africa. Resistance to SP is increasing and associated primarily with mutations in the P. falciparum dhfr (Pfdhfr) and Pfdhps genes. This study aimed to explore the hypothetical association of genetic alterations in the P. falciparum multidrug resistance protein gene (Pfmrp1) with the in vivo response to SP by detecting the selection of single nucleotide polymorphisms (SNPs) following standard single-dose treatment administered to children with acute uncomplicated P. falciparum malaria in Tanzania. We detected significant selection of parasites carrying the Pfmrp1 1466K allele in samples from children with recrudescent infections, with 12 (100%) of 12 such samples being positive for this allele, compared to 52 (67.5%) of 77 baseline samples (P = 0.017), in parallel with the selection of the Pfdhfr Pfdhps quintuple mutant haplotype in cases of recrudescence (P = 0.001). There was no association between the 1466K SNP and the Pfdhfr Pfdhps quintuple mutation, indicating independent selections. Our data point for the first time to a role for a P. falciparum multidrug resistance protein homologue in the antimalarial activity of SP. Moreover, they add to the growing evidence of the potential importance of Pfmrp1 in antimalarial drug resistance.

scholarly journals Andrographolide: A Novel Antimalarial Diterpene Lactone Compound fromAndrographis paniculataand Its Interaction with Curcumin and Artesunate

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Kirti Mishra ◽  
Aditya P. Dash ◽  
Nrisingha Dey
Keyword(s):  
Plasmodium Falciparum ◽  
Life Span ◽  
Plasmodium Berghei ◽  
Antimalarial Activity ◽  
Andrographis Paniculata ◽  
Antiplasmodial Activity ◽  
Template Molecule

Andrographolide (AND), the diterpene lactone compound, was purified by HPLC from the methanolic fraction of the plantAndrographis paniculata. The compound was found to have potent antiplasmodial activity when tested in isolation and in combination with curcumin and artesunate against the erythrocytic stages ofPlasmodium falciparum in vitroandPlasmodium bergheiANKAin vivo. IC50s for artesunate (AS), andrographolide (AND), and curcumin (CUR) were found to be 0.05, 9.1 and 17.4 μM, respectively. The compound (AND) was found synergistic with curcumin (CUR) and addictively interactive with artesunate (AS).In vivo, andrographolide-curcumin exhibited better antimalarial activity, not only by reducing parasitemia (29%), compared to the control (81%), but also by extending the life span by 2-3 folds. Being nontoxic to thein vivosystem this agent can be used as template molecule for designing new derivatives with improved antimalarial properties.

scholarly journals Various Parts of Helianthus annuus Plants as New Sources of Antimalarial Drugs

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Wiwied Ekasari ◽  
Dwi Widya Pratiwi ◽  
Zelmira Amanda ◽  
Suciati ◽  
Aty Widyawaruyanti ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Helianthus Annuus ◽  
Antimalarial Activity ◽  
Ethanol Extract ◽  
The Other ◽  
Antimalarial Agent ◽  
A Value ◽  
Ethanol Extracts

Background. Each part of H. annuus plants is traditionally used as medicinal remedies for several diseases, including malaria. Antimalarial activity of the leaf and the seed has already been observed; however, there is no report about antimalarial activity of the other parts of H. annuus plants. In this study, we assess in vitro and in vivo antimalarial activity of each part of the plants and its mechanism as antimalarial agent against inhibition of heme detoxification. Objective. To investigate the antimalarial activity of various parts of H. annuus. Methods. Various parts of the H. annuus plant were tested for in vitro antimalarial activity against Plasmodium falciparum 3D7 strain (chloroquine-sensitive), in vivo antimalarial activity against P. berghei using Peters’ 4-day suppressive test in BALB/c mice, curative and prophylaxis assay, and inhibition of heme detoxification by evaluating β-hematin level. Results. Ethanol extract of the roots showed the highest antimalarial activity, followed by ethanol extract of leaves, with IC50 values of 2.3 ± 1.4 and 4.3 ± 2.2 μg/mL, respectively and the percentage inhibition of P. berghei of 63.6 ± 8.0 and 59.3 ± 13.2 at a dose of 100 mg/kg, respectively. Ethanol extract of roots produced an ED50 value of 10.6 ± 0.2 mg/kg in the curative test and showed an inhibition of 79.2% at a dose of 400 mg/kg in the prophylactic assay. In inhibition of heme detoxification assay, root and leaf ethanol extracts yielded a lower IC50 value than positive (chloroquine) control with a value of 0.4 ± 0.0 and 0.5 ± 0.0 mg/mL, respectively. Conclusion. There were promising results of the ethanol extracts of root of H. annuus as a new source for the development of a new plant-based antimalarial agent.

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