Effect of protease inhibitors on exflagellation in Plasmodium falciparum

Rupp, Ingrid; Bosse, Rebecca; Schirmeister, Tanja; Pradel, Gabriele

doi:10.1016/j.molbiopara.2007.12.009

Cited by 27 publications

(30 citation statements)

References 18 publications

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“…Tosyllysine chloromethyl ketone hydrochloride (TLCK), an inhibitor of trypsin-like serine proteases, was used as a positive control. TLCK was previously shown to effectively inhibit exflagellation (53,54), and at a concentration of 30 M, it fully blocked the formation of exflagellation centers.…”

Section: Resultsmentioning

confidence: 96%

“…When we assessed the effect of the HDAC inhibitors SAHA and TSA on in vitro male gamete formation, we observed very low inhibitory activity (IC 50 s, 200 to 500 M). Although the exflagellation inhibition activity of compounds is generally markedly lower than that obtained against mature gametocytes (53,74), the exflagellation IC 50 s of SAHA and TSA were at least 600-fold higher than the late-stage gametocyte IC 50 s (Table 1). Likewise, no activity against the in vitro conversion of P. berghei mouse malaria gametocytes to ookinetes was observed.…”

Section: Discussionmentioning

confidence: 94%

“…falciparum exflagellation inhibition assay. Exflagellation assays were carried out according to previously published methods (53)(54)(55). A total volume of 100 l of mature NF54 gametocyte culture was preincubated with SAHA and TSA at concentrations ranging from 0.125 to 2 mM and 0.06 to 0.5 mM, respectively, for 15 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Trenholme

Marek

Duffy

et al. 2014

Antimicrob Agents Chemother

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 94%

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Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Trenholme

Marek

Duffy

et al. 2014

Antimicrob Agents Chemother

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“…Proteasome inhibitors also have not been tested on parasites taken up by a mosquito, while cysteine protease inhibitors have been shown to significantly decrease P. falciparum gamete surface antigen processing, oocyst production, and sporozoite maturation (7, 10). The dual cysteine and serine protease inhibitors L-1-tosylamide-2-phenylethyl-chloromethyl ketone (TPCK) and N␣-p-tosyl-L-lysine chloromethyl ketone (TLCK) also have been reported to reduce P. falciparum exflagellation and the transmission of Plasmodium berghei to mosquitoes (22,26).Genes predicted to code for cysteine proteases and the proteasome are expressed throughout gametocytogenesis, providing targets for both classes of compounds (12,28). Falcipain 1 and the P. berghei orthologs of PfSERA8 (PbECP1) and metacaspase 1 (PbMC1) are the only proteases whose function has been studied directly during gametocytogenesis by targeted gene disruption (3,9,14).…”

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confidence: 99%

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confidence: 99%

The Proteasome Inhibitor Epoxomicin Has Potent Plasmodium falciparum Gametocytocidal Activity

Czesny

Goshu

Cook

2009

Antimicrob Agents Chemother

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Malaria continues to be a major global health problem, but only a limited arsenal of effective drugs is available. None of the antimalarial compounds commonly used clinically kill mature gametocytes, which is the form of the parasite that is responsible for malaria transmission. The parasite that causes the most virulent human malaria, Plasmodium falciparum, has a 48-h asexual cycle, while complete sexual differentiation takes 10 to 12 days. Once mature, stage V gametocytes circulate in the peripheral blood and can be transmitted for more than a week. Consequently, if chemotherapy does not eliminate gametocytes, an individual continues to be infectious for several weeks after the clearance of asexual parasites. The work reported here demonstrates that nanomolar concentrations of the proteasome inhibitor epoxomicin effectively kill all stages of intraerythrocytic parasites but do not affect the viability of human or mouse cell lines. Twenty-four hours after treatment with 100 nM epoxomicin, the total parasitemia decreased by 78%, asexual parasites decreased by 86%, and gametocytes decreased by 77%. Seventy-two hours after treatment, no viable parasites remained in the 100 or 10 nM treatment group. Epoxomicin also blocked oocyst production in the mosquito midgut. In contrast, the cysteine protease inhibitors epoxysuccinyl-L-leucylamido-3-methyl-butane ethyl ester and N-acetyl-L-leucyl-Lleucyl-L-methioninal blocked hemoglobin digestion in early gametocytes but had no effect on later stages. Moreover, once the cysteine protease inhibitor was removed, sexual differentiation resumed. These findings provide strong support for the further development of proteasome inhibitors as antimalaria agents that are effective against asexual, sexual, and mosquito midgut stages of P. falciparum.The current recommended treatments for malaria caused by Plasmodium falciparum, including artemisinin combination therapy, eliminate intraerythrocytic asexual parasites that are responsible for the clinical symptoms. However, these treatments do not kill mature intraerythrocytic gametocytes that are required for the transmission of the parasite (24). In contrast to the 2-day asexual cycle of P. falciparum, the production of a mature stage V gametocyte takes 10 to 12 days. Once mature gametocytes are taken up by a mosquito during a blood meal, fertilization is stimulated. The resulting zygotes develop into oocysts where thousands of sporozoites are produced that can be transmitted to humans during a subsequent blood meal. The prolonged period required for P. falciparum gametocyte maturation in the human host suggests that malaria can be transmitted for several weeks after asexual parasites are eliminated (23). Thus, the development of drugs that are effective against both asexual-stage parasites and gametocytes may directly decrease malaria morbidity and mortality and reduce the spread of the disease.Cysteine protease and proteasome inhibitors have been found to affect asexual intraerythrocytic parasites and are being evaluated as possible an...

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The proteolytic repertoire of malaria parasites

Sijwali

Rosenthal

2016

Advances in Malaria Research

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Effect of protease inhibitors on exflagellation in Plasmodium falciparum

Cited by 27 publications

References 18 publications

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules

The Proteasome Inhibitor Epoxomicin Has Potent Plasmodium falciparum Gametocytocidal Activity

The proteolytic repertoire of malaria parasites

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