Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle

The hemoflagellateTrypanosoma cruziis the causative agent of American trypanosomiasis. Despite the importance of motility in the parasite life cycle, little is known aboutT. cruzimotility, and there is no quantitative description of its flagellar beating. Using video microscopy and quantitative vectorial analysis of epimastigote trajectories, we find a forward parasite motility defined by tip-to-base symmetrical flagellar beats. This motion is occasionally interrupted by base-to-tip highly asymmetric beats, which represent the ciliary beat of trypanosomatid flagella. The switch between flagellar and ciliary beating facilitates the parasite's reorientation, which produces a large variability of movement and trajectories that results in different distance ranges traveled by the cells. An analysis of the distance, speed, and rotational angle indicates that epimastigote movement is not completely random, and the phenomenon is highly dependent on the parasite behavior and is characterized by directed and tumbling parasite motion as well as their combination, resulting in the alternation of rectilinear and intricate motility paths.

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Encounter rate between local populations shapes host selection in complex parasite life cycle

Biological Journal of the Linnean Society ◽

10.1111/j.1095-8312.2006.00661.x ◽

2006 ◽

Vol 89 (1) ◽

pp. 99-106 ◽

Cited By ~ 12

Author(s):

GÉRALDINE LOOT ◽

YOUNG-SEUK PARK ◽

SOVAN LEK ◽

SÉBASTIEN BROSSE

Keyword(s):

Life Cycle ◽

Host Selection ◽

Encounter Rate ◽

Parasite Life Cycle ◽

Local Populations

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Exploratory Analysis into the in vitro and in silico Activity of E. fusca Lour. (Fabaceae) Elucidates Substantial Antiplasmodial Activity of the Plant

10.20944/preprints202010.0576.v2 ◽

2021 ◽

Author(s):

Saiful Arefeen Sazed ◽

Ohedul Islam ◽

Sarah L. Bliese ◽

Muhammad Riadul Haque Hossainey ◽

Jakaria Shawon ◽

...

Keyword(s):

Antimalarial Drug ◽

Simulation Analysis ◽

Antimalarial Activity ◽

Dynamics Simulation ◽

Drug Candidate ◽

Phytochemical Investigation ◽

High Degree ◽

Emergence Of Resistance ◽

First Time

The exploration of alternative antimalarial therapeutics is a requisite for the emergence of resistance against Artemisinin. Considering the required cost and time length of classical small molecule drug discovery process, phytochemical screening of traditionally used medicinal plant which are repertoire of active compounds with antimalarial activity has become popular. To investigate the antimalarial property of traditionally used medicinal plants, a number of Erythrina spp have been reviewed systematically where less studied E. fusca has been selected for further analysis. Phytochemical investigation yielded five compounds namely; Phaseolin, Phytol, β-amyrin, Lupeol, and Stigmasterol. In-vitro antimalarial drug sensitivity HRP-II ELISA was carried out against chloroquine (CQ) sensitive 3D7 and CQ-resistant Dd2 strains. Extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC50 4.94 – 22 µg/mL) and these compounds have been reported here for the first time. Molecular docking analysis showed high binding energy (−9.0 ± 0.32 kcal/mole) indicating high degree of interaction between Phaseolin and 14 clinically important Plasmodium falciparum proteins at the active site. Stable interaction was also observed between ligand and protein from molecular dynamics simulation analysis with high free energy (−75.156 ± 11.459) that substantiates the potential of Phaseolin as an antimalarial drug candidate.

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Structural, functional and computational studies of membrane recognition by Plasmodium Perforin-Like Proteins 1 and 2.

10.1101/2021.12.16.473088 ◽

2021 ◽

Author(s):

Sophie Williams ◽

Xiulian Yu ◽

Tao Ni ◽

Robert Gilbert ◽

Phillip Stansfeld

Keyword(s):

Life Cycle ◽

Lipid Bilayers ◽

Membrane Binding ◽

Binding Activity ◽

Life Cycles ◽

Site Directed Mutagenesis ◽

Parasite Life Cycle ◽

Dynamics Simulations ◽

Membrane Recognition

Perforin-like proteins (PLPs) play key roles in the mechanisms associated with parasitic disease caused by apicomplexans such as Plasmodium (malaria) and Toxoplasma. The T. gondii PLP1 (TgPLP1) mediates tachyzoite egress from cells, while the five Plasmodium PLPs carry out various roles in the life cycle of the parasite and with respect to the molecular basis of disease. Here we focus on Plasmodium vivax PLP1 and PLP2 (PvPLP1 and PvPLP2) compared to TgPLP1; PvPLP1 is important for invasion of mammalian hosts by the parasite and establishment of a chronic infection, PvPLP2 is important during the symptomatic blood stage of the parasite life cycle. Determination of the crystal structure of the membrane-binding APCβ domain of PvPLP1 reveals notable differences with that of TgPLP1, which are reflected in its inability to bind lipid bilayers in the way that TgPLP1 and PvPLP2 can be shown to. Molecular dynamics simulations combined with site-directed mutagenesis and functional assays allow a dissection of the binding interactions of TgPLP1 and PvPLP2 on lipid bilayers, and reveal a similar tropism for lipids found enriched in the inner leaflet of the mammalian plasma membrane. In addition to this shared mode of membrane binding PvPLP2 displays a secondary synergistic interaction side-on from its principal bilayer interface. This study underlines the substantial differences between the biophysical properties of the APCβ domains of Apicomplexan PLPs, which reflect their significant sequence diversity. Such differences will be important factors in determining the cell targeting and membrane-binding activity of the different proteins, in their different developmental roles within parasite life cycles.

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Furuncular Botfly Myiasis – A Case Report

Serbian Journal of Dermatology and Venerology ◽

10.2478/sjdv-2018-0002 ◽

2018 ◽

Vol 10 (1) ◽

pp. 9-11

Author(s):

Juliana Gao ◽

Vera Tešić ◽

Vesna Petronić Rosić

Keyword(s):

Case Report ◽

Life Cycle ◽

South America ◽

Treatment Options ◽

Local Population ◽

Body Cavity ◽

Parasite Life Cycle ◽

Susceptible Host ◽

Dermatobia Hominis ◽

Blood Sucking

Abstract Botfly myiasis is an infestation of the skin or a body cavity by developing larvae of Dermatobia hominis, one of the most common flies that cause human infestation among the local population, in regions ranging from Mexico into South America and in travelers. The life cycle starts when a female fly glues the eggs to the vector, a blood-sucking arthropod, which carries the unhatched larvae to the susceptible host. A case of furuncular botfly myiasis in an 85 year-old female with recent travel to Belize is presented here to highlight the parasite life cycle and review the different treatment options.

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Contribution to the Improvement of an Oral Formulation of Niclosamide, an Antihelmintic Drug Candidate for Repurposing in SARS-CoV-2 and Other Viruses

10.26434/chemrxiv.12056187.v1 ◽

2020 ◽

Author(s):

Eduardo José Barbosa ◽

Mariana Ribeiro Gubitoso ◽

Nádia Araci Bou-Chacra ◽

Stephen R. Byrn ◽

Flavio M. S. Carvalho ◽

...

Keyword(s):

Solid Dispersions ◽

Amorphous Solid ◽

Aqueous Solubility ◽

Oral Formulation ◽

Oral Dosage ◽

Drug Candidate ◽

Formulation Development ◽

Polymer Dispersions ◽

Kinetic Solubility ◽

Oral Dosage Forms

<p>Niclosamide (NCL) is an effective anthelmintic agent that has been shown to possess broad-spectrum antiviral activity, including against<b> </b>SARS-CoV-2. Due to its poor solubility in aqueous medium, however, the commercially available NCL formulations can act only locally in gastrointestinal worms and are not suitable to achieve plasmatic levels to treat systemic diseases. Consequently, the repurposing of this drug represents a challenge for formulation development with serious risks to the biological availability and can compromise preclinical and clinical outcomes. Herein, we report possible formulation, through the research and development, of stable amorphous solid dispersions to improve its solubility. The results of exploratory screening of NCL-polymer dispersions (performed through X-ray powder diffraction and kinetic solubility studies) indicate that soluplus-niclosamide dispersions can increase its aqueous solubility and, consequently, have the potential to enhance NCL bioavailability. <a>This outcome can be used for the development of oral dosage forms for clinical trials in SARS-CoV-2 and other viruses. </a></p>

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A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03342-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 356-364 ◽

Cited By ~ 52

Author(s):

Wesley Wu ◽

Zachary Herrera ◽

Danny Ebert ◽

Katie Baska ◽

Seok H. Cho ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Antimalarial Drug ◽

Drug Targets ◽

Specific Activity ◽

Drug Candidate ◽

Content Type ◽

Chemical Rescue ◽

Growth Inhibitory ◽

Parasite Populations

ABSTRACTThe apicoplast is an essential plastid organelle found inPlasmodiumparasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the “Malaria Box” library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stagePlasmodium falciparumgrowth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations inP. falciparumIspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activityin vitrowith a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.

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