Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria

Li, Xuerong; Chen, Huiqing; Bahamontes-Rosa, Noemi; Kun, Jürgen F. J.; Traoré, Boubacar; Crompton, Peter D.; Chishti, Athar H.

doi:10.1016/j.bbrc.2009.01.083

Cited by 45 publications

(49 citation statements)

References 17 publications

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“…3A). Initially, we envisioned that we would build this assay in P. falciparum; however, genetic tractability was severely limiting, and PfSPP is an essential gene, so perturbations to this protein are lethal to the organism (33). To circumvent this difficulty, we designed the assay in the budding yeast Saccharomyces cerevisiae because of the genetic manipulability of this system and because S. cerevisiae contains no PS orthologue (thus yielding lower potential background signal) and only a single SPP gene (rather than five as in mammalian cells).…”

Section: Spp Inhibitors Directly Block Pfspp Activity In Heterologousmentioning

confidence: 99%

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

Harbut

Patel

Yeung

et al. 2012

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

110

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Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin-and proteasome-mediated process known as ER-associated degradation (ERAD). Protozoan pathogens, including the causative agents of malaria, toxoplasmosis, trypanosomiasis, and leishmaniasis, contain a minimal ERAD network relative to higher eukaryotic cells, and, because of this, we observe that the malaria parasite Plasmodium falciparum is highly sensitive to the inhibition of components of this protein quality control system. Inhibitors that specifically target a putative protease component of ERAD, signal peptide peptidase (SPP), have high selectivity and potency for P. falciparum. By using a variety of methodologies, we validate that SPP inhibitors target P. falciparum SPP in parasites, disrupt the protein's ability to facilitate degradation of unstable proteins, and inhibit its proteolytic activity. These compounds also show low nanomolar activity against liver-stage malaria parasites and are also equipotent against a panel of pathogenic protozoan parasites. Collectively, these data suggest ER quality control as a vulnerability of protozoan parasites, and that SPP inhibition may represent a suitable transmission blocking antimalarial strategy and potential panprotozoan drug target.intramembrane proteolysis | small molecule | target validation

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Section: Spp Inhibitors Directly Block Pfspp Activity In Heterologousmentioning

confidence: 99%

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

Harbut

Patel

Yeung

et al. 2012

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

110

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“…Artemisinin and its derivatives may be our last line of drug defense, although recent reports have indicated signs of reduced effectiveness of artemisinin combination therapies (ACTs) (23,28). For the development of the next generation of antimalarial agents, new targets and pathways susceptible to interruption by chemotherapy need to be identified.The asexual intraerythrocytic stages of Plasmodium development are responsible for the clinical symptoms attributable to malaria, and most antimalarial drugs target these stages of the parasite's life cycle (15,30). Many laboratories have focused on the hydrolytic process of hemoglobin (Hb) digestion within the parasite's specialized digestive vacuole as a target for drug discovery (4,7,16,18,32).…”

mentioning

confidence: 99%

“…The asexual intraerythrocytic stages of Plasmodium development are responsible for the clinical symptoms attributable to malaria, and most antimalarial drugs target these stages of the parasite's life cycle (15,30). Many laboratories have focused on the hydrolytic process of hemoglobin (Hb) digestion within the parasite's specialized digestive vacuole as a target for drug discovery (4,7,16,18,32).…”

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confidence: 99%

The Aminopeptidase Inhibitor CHR-2863 Is an Orally Bioavailable Inhibitor of Murine Malaria

Skinner‐Adams

Peatey

Anderson

et al. 2012

Antimicrob Agents Chemother

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g Malaria remains a significant risk in many areas of the world, with resistance to the current antimalarial pharmacopeia an everincreasing problem. The M1 alanine aminopeptidase (PfM1AAP) and M17 leucine aminopeptidase (PfM17LAP) are believed to play a role in the terminal stages of digestion of host hemoglobin and thereby generate a pool of free amino acids that are essential for parasite growth and development. Here, we show that an orally bioavailable aminopeptidase inhibitor, CHR-2863, is efficacious against murine malaria. Malaria is a major cause of morbidity and mortality worldwide, with as many as 1 million deaths each year (3). While four Plasmodium species commonly infect humans, malaria caused by Plasmodium falciparum is responsible for most deaths, particularly in children under the age of 5 and pregnant women (2, 24). Both prevention and treatment of P. falciparum malaria are under threat because of the spread of drug-resistant parasites. Resistance to chloroquine is now considered almost universal (36), while the efficacy of affordable antimalarial drugs, such as sulfadoxine-pyrimethamine, the major drug used for intermittent preventative therapy, is declining (19,22). Artemisinin and its derivatives may be our last line of drug defense, although recent reports have indicated signs of reduced effectiveness of artemisinin combination therapies (ACTs) (23,28). For the development of the next generation of antimalarial agents, new targets and pathways susceptible to interruption by chemotherapy need to be identified.The asexual intraerythrocytic stages of Plasmodium development are responsible for the clinical symptoms attributable to malaria, and most antimalarial drugs target these stages of the parasite's life cycle (15,30). Many laboratories have focused on the hydrolytic process of hemoglobin (Hb) digestion within the parasite's specialized digestive vacuole as a target for drug discovery (4,7,16,18,32). During the asexual development phase, malaria parasites degrade 65 to 75% of their host cell's Hb, a process that ultimately results in the release of amino acids that are used by the parasite for protein anabolism (29) and the maintenance of osmotic pressure within the infected erythrocyte (14). Two metalloaminopeptidase enzymes, the P. falciparum M1 alanine aminopeptidase (PfM1AAP) and the P. falciparum M17 leucine aminopeptidase (PfM17LAP), may be critical in the terminal stages of Hb degradation and the release of free amino acids (6, 21). We have shown that inhibitors of these aminopeptidases, such as the natural Phe-Leu dipeptide analog bestatin, derived from the fungus Streptomyces olivoretticuli, and several synthetic phosphinate dipeptide analogs, can kill P. falciparum parasites in culture. These compounds are also effective against the rodent malaria parasite Plasmodium chabaudi chabaudi in vivo when administered intraperitoneally (i.p.) (32,33). We have also recently reported the production and characterization of functionally active recombinant P. falciparum M1 alanine aminopeptidas...

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“…Proteases have long been considered viable drug targets. Recent studies have identified a single gene encoded aspartic protease essential for parasite development and survival [2,3,4,5]. This enzyme termed Plasmodium falciparum signal peptide peptidase (PfSPP) may serve as a promising drug target; however, its precise cellular function and natural substrates are not yet known.…”

Section: Introductionmentioning

confidence: 99%

Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis

Baldwin

Russo

et al. 2014

Biochemical and Biophysical Research Communications

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Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of Plasmodium falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle.

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Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria

Cited by 45 publications

References 17 publications

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design

The Aminopeptidase Inhibitor CHR-2863 Is an Orally Bioavailable Inhibitor of Murine Malaria

Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis

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