Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B

Reynolds, Jennifer M.; Bissati, Kamal El; Brandenburg, Jens; Günzl, Arthur; Mamoun, Choukri Ben

doi:10.1186/1472-6904-7-13

Cited by 64 publications

(55 citation statements)

References 24 publications

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“…However, we suspect Pf-LAP may have an essential housekeeping function in the cytosolic turnover of dipeptides (49) and perhaps acts in concert with the parasite proteasome, as has been shown for other neutral cytosolic leucine aminopeptidases pathways (50). Like PNAP, lethal amounts of proteasome inhibitors exert their effect in the ring-trophozoite transition and parasites do not progress into the later trophozoite stage (51). Our data does not completely rule out the possibility of a minor role for Pf-LAP in the Hb degradation pathway via proteolysis of Hb-derived dipeptides that have been transported from the DV into the cytoplasm.…”

Section: Discussionmentioning

confidence: 57%

Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases

Harbut

Velmourougane

Dalal

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

176

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Malaria causes worldwide morbidity and mortality, and while chemotherapy remains an excellent means of malaria control, drug-resistant parasites necessitate the discovery of new antimalarials. Peptidases are a promising class of drug targets and perform several important roles during the Plasmodium falciparum erythrocytic life cycle. Herein, we report a multidisciplinary effort combining activity-based protein profiling, biochemical, and peptidomic approaches to functionally analyze two genetically essential P. falciparum metallo-aminopeptidases (MAPs), PfA-M1 and Pf-LAP. Through the synthesis of a suite of activity-based probes (ABPs) based on the general MAP inhibitor scaffold, bestatin, we generated specific ABPs for these two enzymes. Specific inhibition of PfA-M1 caused swelling of the parasite digestive vacuole and prevented proteolysis of hemoglobin (Hb)-derived oligopeptides, likely starving the parasite resulting in death. In contrast, inhibition of Pf-LAP was lethal to parasites early in the life cycle, prior to the onset of Hb degradation suggesting that Pf-LAP has an essential role outside of Hb digestion.protease | chemical-genetics | proteomics | small molecule | drug design

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Section: Discussionmentioning

confidence: 57%

Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases

Harbut

Velmourougane

Dalal

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

176

View full text Add to dashboard Cite

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“…248 Results showed that these boronate protease inhibitors disrupted the cell cycle prior to DNA synthesis but had no effect on parasite egress at the late schizont stage or subsequent erythrocyte invasion. In order to evaluate the antimalarial activity of some known proteasome inhibitors, Kreidenweiss and co-workers tested a few of these specific inhibitors, YU101, MG132, Ada-Ahx 3 -L 3 -VS, Z-L 3 -VS and epoxomicin (Table 1), against CQ-resistant (Dd2) and CQ-sensitive (3D7 and D10) P. falciparum strains.…”

Section: Antitumoralsmentioning

confidence: 99%

“Recycling” Classical Drugs for Malaria

et al. 2014

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“…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 antimalarial agents (4,7,10,15,(19)(20)(21)25). However, their effect on the 10-to 12-day course of intraerythrocytic gametocyte development has not been reported.…”

mentioning

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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Antimalarial activity of the anticancer and proteasome inhibitor bortezomib and its analog ZL3B

Cited by 64 publications

References 24 publications

Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases

Bestatin-based chemical biology strategy reveals distinct roles for malaria M1- and M17-family aminopeptidases

“Recycling” Classical Drugs for Malaria

The Proteasome Inhibitor Epoxomicin Has Potent Plasmodium falciparum Gametocytocidal Activity

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