Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum

2021 ◽  
Author(s):  
Aloysus Lawong ◽  
Suraksha Gahalawat ◽  
John Okombo ◽  
Josefine Striepen ◽  
Tomas Yeo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Degradation Pathway ◽  
Hemoglobin Degradation

scholarly journals Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway.

1994 ◽  
Vol 93 (4) ◽  
pp. 1602-1608 ◽  
Author(s):  
I Y Gluzman ◽  
S E Francis ◽  
A Oksman ◽  
C E Smith ◽  
K L Duffin ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Degradation Pathway ◽  
Hemoglobin Degradation

scholarly journals An essential vesicular-trafficking phospholipase mediates neutral lipid synthesis and contributes to hemozoin formation in Plasmodium falciparum

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mohd Asad ◽  
Yoshiki Yamaryo-Botté ◽  
Mohammad E. Hossain ◽  
Vandana Thakur ◽  
Shaifali Jain ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Neutral Lipid ◽  
Neutral Lipids ◽  
Lipid Synthesis ◽  
Large Family ◽  
Degradation Pathway ◽  
Food Vacuole ◽  
Parasite Growth ◽  
Lipid Homeostasis ◽  
Parasite Development

Abstract Background Plasmodium falciparum is the pathogen responsible for the most devastating form of human malaria. As it replicates asexually in the erythrocytes of its human host, the parasite feeds on haemoglobin uptaken from these cells. Heme, a toxic by-product of haemoglobin utilization by the parasite, is neutralized into inert hemozoin in the food vacuole of the parasite. Lipid homeostasis and phospholipid metabolism are crucial for this process, as well as for the parasite’s survival and propagation within the host. P. falciparum harbours a uniquely large family of phospholipases, which are suggested to play key roles in lipid metabolism and utilization. Results Here, we show that one of the parasite phospholipase (P. falciparum lysophospholipase, PfLPL1) plays an essential role in lipid homeostasis linked with the haemoglobin degradation and heme conversion pathway. Fluorescence tagging showed that the PfLPL1 in infected blood cells localizes to dynamic vesicular structures that traffic from the host-parasite interface at the parasite periphery, through the cytosol, to get incorporated into a large vesicular lipid rich body next to the food-vacuole. PfLPL1 is shown to harbour enzymatic activity to catabolize phospholipids, and its transient downregulation in the parasite caused a significant reduction of neutral lipids in the food vacuole-associated lipid bodies. This hindered the conversion of heme, originating from host haemoglobin, into the hemozoin, and disrupted the parasite development cycle and parasite growth. Detailed lipidomic analyses of inducible knock-down parasites deciphered the functional role of PfLPL1 in generation of neutral lipid through recycling of phospholipids. Further, exogenous fatty-acids were able to complement downregulation of PfLPL1 to rescue the parasite growth as well as restore hemozoin levels. Conclusions We found that the transient downregulation of PfLPL1 in the parasite disrupted lipid homeostasis and caused a reduction in neutral lipids essentially required for heme to hemozoin conversion. Our study suggests a crucial link between phospholipid catabolism and generation of neutral lipids (TAGs) with the host haemoglobin degradation pathway.

scholarly journals A malarial cysteine proteinase is necessary for hemoglobin degradation by Plasmodium falciparum.

1988 ◽  
Vol 82 (5) ◽  
pp. 1560-1566 ◽  
Author(s):  
P J Rosenthal ◽  
J H McKerrow ◽  
M Aikawa ◽  
H Nagasawa ◽  
J H Leech
Keyword(s):  
Plasmodium Falciparum ◽  
Cysteine Proteinase ◽  
Hemoglobin Degradation

The role of hemoglobin degradation pathway in preeclampsia: A systematic review and meta-analysis

Placenta ◽  
2020 ◽  
Vol 92 ◽  
pp. 9-16 ◽  
Author(s):  
Ioannis Bellos ◽  
Vasilios Pergialiotis ◽  
Dimitrios Loutradis ◽  
Angeliki Papapanagiotou ◽  
Georgios Daskalakis
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Degradation Pathway ◽  
Hemoglobin Degradation

scholarly journals Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7

2016 ◽  
Vol 113 (8) ◽  
pp. 2080-2085 ◽  
Author(s):  
Hanafy M. Ismail ◽  
Victoria Barton ◽  
Matthew Phanchana ◽  
Sitthivut Charoensutthivarakul ◽  
Michael H. L. Wong ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Targets ◽  
Antioxidant Defense ◽  
Protein Profiling ◽  
Parasite Protein ◽  
Know How ◽  
Parasite Survival ◽  
Hemoglobin Degradation ◽  
Insight Into

The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography–MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.

Combined CADD and Virtual Screening to Identify Novel Nonpeptidic Falcipain-2 Inhibitors

2020 ◽  
Vol 16 ◽  
Author(s):  
Trisha Rajguru ◽  
Dipshikha Bora ◽  
Mahendra Kumar Modi
Keyword(s):  
Plasmodium Falciparum ◽  
Life Cycle ◽  
Radius Of Gyration ◽  
Computer Aided Drug Design ◽  
Discovery Studio ◽  
Pubchem Database ◽  
Starting Point ◽  
New Type ◽  
Hemoglobin Degradation ◽  
Antimalarial Chemotherapy

Background: : Plasmodium falciparum is the most dangerous and widespread disease-causing species of malaria. Falcipain-2 (FP2) of Plasmodium falciparum, is a potential target for antimalarial chemotherapy since it is involved in an essential cellular function such as hemoglobin degradation during the parasite’s life cycle. However, despite their central role in the life cycle of the parasite, no commercial drug targeting Falcipain-2 has been developed to date. Prior efforts to develop peptide-based drugs against Plasmodium have been futile due to their susceptibility to being degraded by host enzymes. Objective:: Here we report computer-aided drug design of new nonpeptidic inhibitors against FP2, which are likely to be safe from degradation by host enzymes. Method: : We have virtually screened for the probable FP2 inhibitors from the PubChem database by submitting the wellequilibrated 3-D structure of FP2. Furthermore, virtual screenings and dockings were carried out using PyRx and Discovery Studio. Result: : We found 15 top-ranking molecules with carbaldehyde pharmacophore having a good fit with the target protein. Based on the C-Docker values, the top 4 hits (PubChem 44138738, PubChem 20983198, PubChem 20983081 and PubChem 28951461) for FP2 were identified. These four hits have been observed to bound to the active cleft of the protein. Moreover, their complexes were also found to be stable from the RMSD and Radius of Gyration analysis. Conclusion:: The selected compounds 2-(benzylamino)-8-methylquinoline-3-carbaldehyde (PubChem44138738), 6- bromo-2-(3,4-dihydro-1H-isoquinolin-2-yl)quinoline-3-carbaldehyde (PubChem 20983198), 2-(3,4-dihydro-1Hisoquinolin-2-yl)-6-ethylquinoline-3-carbaldehyde(PubChem20983081)and 2-[benzyl(methyl)amino]quinoline-3- carbaldehyde (PubChem 28951461) may be the starting point for further modification as a new type of nonpeptidic drug for malaria disease.

Identification of hemoglobin degradation products in Plasmodium falciparum

1997 ◽  
Vol 86 (2) ◽  
pp. 179-186 ◽  
Author(s):  
S Kamchonwongpaisan ◽  
E Samoff ◽  
S.R Meshnick
Keyword(s):  
Plasmodium Falciparum ◽  
Degradation Products ◽  
Hemoglobin Degradation

scholarly journals Blocking Plasmodium falciparum Development via Dual Inhibition of Hemoglobin Degradation and the Ubiquitin Proteasome System by MG132

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e73530 ◽  
Author(s):  
Rajesh Prasad ◽  
Atul ◽  
Venkata Karunakar Kolla ◽  
Jennifer Legac ◽  
Neha Singhal ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome ◽  
Dual Inhibition ◽  
Hemoglobin Degradation

Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors.

1996 ◽  
Vol 40 (7) ◽  
pp. 1600-1603 ◽  
Author(s):  
P J Rosenthal ◽  
J E Olson ◽  
G K Lee ◽  
J T Palmer ◽  
J L Klaus ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Metabolic Activity ◽  
Proteinase Inhibitors ◽  
Cysteine Proteinase ◽  
Vinyl Sulfone ◽  
Antimalarial Agents ◽  
Cysteine Proteinase Inhibitors ◽  
Hemoglobin Degradation

We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development. The antimalarial effects correlated with the inhibition of falcipain. Our results suggest that vinyl sulfones or related cysteine proteinase inhibitors may have promise as antimalarial agents.

Sign in / Sign up

Export Citation Format

Share Document