Plasmepsin Inhibitors in Antimalarial Drug Discovery: Medicinal Chemistry and Target Validation (2000 to Present)

Cheuka, Peter Mubanga; Dziwornu, Godwin Akpeko; Okombo, John; Chibale, Kelly

doi:10.1021/acs.jmedchem.9b01622

Cited by 30 publications

(24 citation statements)

References 95 publications

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“…Additionally, clinically used HIV protease inhibitors such as lopinavir have been investigated in detail, although their clinical antimalarial efficacy is likely to be marginal. The inhibitor literature has been reviewed elsewhere (8,180,181) and is beyond the scope of this article. Here, we will instead focus on implications of the biology of plasmepsins for drug development.…”

Section: Plasmepsins As Drug Targetsmentioning

confidence: 99%

Malaria parasite plasmepsins: More than just plain old degradative pepsins

Nasamu¹,

Polino²,

Istvan

et al. 2020

Journal of Biological Chemistry

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Plasmepsins are a group of diverse aspartic proteases in the malaria parasite Plasmodium. Their functions are strikingly multifaceted, ranging from hemoglobin degradation to secretory organelle protein processing for egress, invasion, and effector export. Some, particularly the digestive vacuole plasmepsins, have been extensively characterized, whereas others, such as the transmission-stage plasmepsins, are minimally understood. Some (e.g. plasmepsin V) have exquisite cleavage sequence specificity; others are fairly promiscuous. Some have canonical pepsin-like aspartic protease features, whereas others have unusual attributes, including the nepenthesin loop of plasmepsin V and a histidine in place of a catalytic aspartate in plasmepsin III. We have learned much about the functioning of these enzymes, but more remains to be discovered about their cellular roles and even their mechanisms of action. Their importance in many key aspects of parasite biology makes them intriguing targets for antimalarial chemotherapy. Further consideration of their characteristics suggests that some are more viable drug targets than others. Indeed, inhibitors of invasion and egress offer hope for a desperately needed new drug to combat this nefarious organism.

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Section: Plasmepsins As Drug Targetsmentioning

confidence: 99%

Malaria parasite plasmepsins: More than just plain old degradative pepsins

Nasamu¹,

Polino²,

Istvan

et al. 2020

Journal of Biological Chemistry

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“…The two Plasmodium enzymes were plasmepsin II (PDB code 4cku) involved in haemoglobin metabolism by the parasite, and P. falciparum l-lactate dehydrogenase (pfLDH) (PDB code 1ldg) involved in glycolysis (or glucose metabolism of the parasite) [ 55 – 57 ]. There is a strong suggestion that haemoglobin digesting enzymes found in the food vacuole of the Plasmodium and pfLDH are potential anti-malarial chemotherapeutic targets for chloroquine and related aminoquionlones, anthraquinones and other oxidative phenolic compounds [ 58 – 63 ]. Gossypol and other phenolic compounds were also found to be pfLDH inhibitors [ 64 , 65 ].…”

Section: Resultsmentioning

confidence: 99%

In vivo anti-malarial activity of the hydroalcoholic extract of rhizomes of Kniphofia foliosa and its constituents

Alebachew

Bisrat

Tadesse

et al. 2021

Malar J

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Background Kniphofia foliosa is a flamboyant robust perennial herb which has dense clumps and tick upright rhizomes with leaves at the base. In Ethiopia, it has several vernacular names including Abelbila, Ashenda, Amelmela, Yeznjero Ageda, Shemetmetie and Yezinjero Ageda. The plant is endemic to Ethiopian highlands, where its rhizomes are traditionally used for the treatment of malaria, abdominal cramps and wound healing. In the present study, the 80% methanol extract of K. foliosa rhizomes and its constituents are tested against Plasmodium berghei in mice. Methods Isolation was carried out using column and preparative thin layer chromatography (PTLC). The chemical structures of the compounds were elucidated by spectroscopic methods (ESI–MS, 1D and 2D-NMR). Peters’ 4-day suppressive test against P. berghei in mice was utilized for in vivo anti-malarial evaluation of the test substances. Results Two compounds, namely knipholone and dianellin were isolated from the 80% methanolic extract of K. foliosa rhizomes, and characterized. The hydroalcoholic extract (400 mg/kg) and knipholone (200 mg/kg) showed the highest activity with chemosuppression values of 61.52 and 60.16%, respectively. From the dose–response plot, the median effective (ED50) doses of knipholone and dianellin were determined to be 81.25 and 92.31 mg/kg, respectively. Molecular docking study revealed that knipholone had a strong binding affinity to Plasmodium falciparum l-lactate dehydrogenase (pfLDH) target. Conclusion Results of the current study support the traditional use of the plant for the treatment of malaria.

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“…Plasmepsins (especially PlmII, PlmIV, PlmV, PlmIX and X) are drug targets for malaria. 107,108 Artemisinin and chloroquine are the two major blockbuster drugs against malaria. Emergence of artemisinin 109 and chloroquine 110 resistant P. falciparum possess a huge risk towards eradication efforts towards malaria in Africa and South-East Asia.…”

Section: Ideal Playing Eld For Drug Repurposingmentioning

confidence: 99%