Falcipains: Biochemistry, target validation and structure-activity relationship studies of inhibitors as antimalarials

Patra, Jeevan; Rana, Devika; Arora, Smriti; Pal, Mintu; Mahindroo, Neeraj

doi:10.1016/j.ejmech.2023.115299

Cited by 4 publications

(5 citation statements)

References 118 publications

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“…Cysteine proteases activity and their regulation (for example, by the inhibitors of cysteine proteases, ICP) are important in the blood stage of human and rodent malaria [ 130 , 131 , 132 , 133 ], in the liver stage in the host for parasite–hepatocyte intertalk during exoerythrocytic merozoite release [ 133 ], and in Plasmodium sporozoite egress from oocysts [ 29 ] (see also the Section 2.5 ). More specifically, cysteine proteases falcipain-2 and -3 are principally involved in hemoglobin digestion [ 130 , 131 , 134 ], and falcipain-1 plays a major role in merozoite invasion [ 130 , 131 ]. P.f.…”

Section: Protein Ptms In Plasmodium Parasite Growt...mentioning

confidence: 99%

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Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Schwarzer,

Skorokhod

2024

IJMS

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Post-translational modifications (PTMs) are essential for regulating protein functions, influencing various fundamental processes in eukaryotes. These include, but are not limited to, cell signaling, protein trafficking, the epigenetic control of gene expression, and control of the cell cycle, as well as cell proliferation, differentiation, and interactions between cells. In this review, we discuss protein PTMs that play a key role in the malaria parasite biology and its pathogenesis. Phosphorylation, acetylation, methylation, lipidation and lipoxidation, glycosylation, ubiquitination and sumoylation, nitrosylation and glutathionylation, all of which occur in malarial parasites, are reviewed. We provide information regarding the biological significance of these modifications along all phases of the complex life cycle of Plasmodium spp. Importantly, not only the parasite, but also the host and vector protein PTMs are often crucial for parasite growth and development. In addition to metabolic regulations, protein PTMs can result in epitopes that are able to elicit both innate and adaptive immune responses of the host or vector. We discuss some existing and prospective results from antimalarial drug discovery trials that target various PTM-related processes in the parasite or host.

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Section: Protein Ptms In Plasmodium Parasite Growt...mentioning

confidence: 99%

“…For example, cysteine proteases P.f. falcipains were reviewed as drug target [ 134 ]. Interestingly, the pro-oxidant action of dihydroartemisinin was recently connected to P.f.…”

Section: Antimalarials and Protein Modificationsmentioning

confidence: 99%

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Schwarzer,

Skorokhod

2024

IJMS

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“…Therefore, it is advantageous for novel antimalarial drugs to be able to target these associated proteins and have a good pharmacokinetic profile. A class of imine medicines known as phenylhydrazones has been shown to have powerful antimalarial properties by blocking the heme to haemazoin pathway and killing P. falciparum [ 8 , 9 ]. These include novel target proteins for antimalarials including the Plasmodium kinome, food vacuole, cysteine proteases, and aminopeptidases.…”

Section: Introductionmentioning

confidence: 99%

N-Substituted Phenylhydrazones Kill the Ring Stage of Plasmodium falciparum

Amengor,

Biniyam,

Brobbey

et al. 2024

BioMed Research International

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Antimalarial resistance has hampered the effective treatment of malaria, a parasitic disease caused by Plasmodium species. As part of our campaign on phenotypic screening of phenylhydrazones, a library of six phenylhydrazones was reconstructed and evaluated for their in vitro antimalarial and in silico receptor binding and pharmacokinetic properties. The structures of the phenylhydrazone hybrids were largely confirmed using nuclear magnetic resonance techniques. We identified two compounds which exhibited significant antimalarial potential against the ring stage (trophozoite) of 3D7 chloroquine-sensitive (CS) strain and DD2 chloroquine-resistant (CR) strains of Plasmodium falciparum with monosubstituted analogs bearing meta or para electron-donating groups showing significant activity in the single-digit micromolar range. Structure activity relationship is presented showing that electron-donating groups on the substituent hydrophobic pharmacophore are required for antimalarial activity. Compounds PHN6 and PHN3 were found to be the most potent with pIC50s (calculated form in vitro IC50s) of 5.37 and 5.18 against 3D7 CS and DD2 CR strains, respectively. Our selected ligands (PHN3 and PHN6) performed better when compared to chloroquine regarding binding affinity and molecular stability with the regulatory proteins of Plasmodium falciparum, hence predicted to be largely responsible for their in vitro activity. Pharmacokinetic prediction demonstrated that the phenylhydrazones may not cross the blood-brain barrier and are not P-glycoprotein (P-gp) substrates, a good absorption of 62% to 69%, and classified as a category IV compound based on toxicity grading.

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“…Cysteine protease inhibitors such as fluoromethyl ketone (highly selective and potent inhibitor of FP-2) are being discovered for development of anti-malarial agents. [15] The anti-malarial agents which are in pipeline or clinical trials for preclinical, clinical and marketing surveillance (Phase IV) studies for the development of anti-malarial drugs have been presented in Figure 2. [16] It can be speculated that rather than an individual drugs, the combination of more than one drugs can be effective solution to development of anti-malarial therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

Dhameliya,

Patel,

Kathuria

et al. 2024

ChemistrySelect

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Malaria remains a severe infectious disease caused by Plasmodium parasites among the primarily afflicting impoverished populations. According to World Health Organization (WHO) report, there were an estimated 247 million malarial cases globally, resulting in approximately 6,19,000 fatalities. Particularly prevalent in tropical and subtropical regions, the development of drug resistance has exacerbated this public health challenge. Consequently, there has been a concrete effort to explore novel compounds with anti‐malarial properties. In continuation of our previous works, this review focuses on heterocyclic compounds documented in 2021 and 2022, including artemisinin, benzimidazole, benzofuran, β‐lactam, coumarin, furan, indole, morpholine, piperazine, pyrimidine, quinoline, triazole, etc. highlighting their efficacy, structural characteristics, in vitro and in vivo activities, among other relevant aspects for the broad interest of medicinal chemists working on the design and development of novel anti‐malarial agents.

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Falcipains: Biochemistry, target validation and structure-activity relationship studies of inhibitors as antimalarials

Cited by 4 publications

References 118 publications

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

Post-Translational Modifications of Proteins of Malaria Parasites during the Life Cycle

N-Substituted Phenylhydrazones Kill the Ring Stage of Plasmodium falciparum

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

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