BDA-410: A novel synthetic calpain inhibitor active against blood stage malaria

Li, Xuerong; Chen, Huiqing; Jeong, Jong-Jin; Chishti, Athar H.

doi:10.1016/j.molbiopara.2007.05.004

Cited by 25 publications

(32 citation statements)

References 37 publications

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“…23 Band 3 null and protein 4.2 null mice (2-3 months old) were challenged with the rodent P yoelii 17XL infection (blood stage), essentially as described previously. 24 Wild-type C57BL/6 mice and agematched heterozygous littermates were used as controls.…”

Section: Infection Of Band 3 and Protein 42 Null Mice By P Yoelii 17xlmentioning

confidence: 99%

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

Baldwin

Hanada

et al. 2015

Blood

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• The N-terminal subunit of MSP1 binds to a specific polypeptide region of GPA during merozoite invasion of human RBCs.• The GPA-band 3 complex plays an essential role during malaria parasite invasion.Plasmodium falciparum invasion of human red blood cells (RBCs) is an intricate process requiring a number of distinct ligand-receptor interactions at the merozoite-erythrocyte interface. Merozoite surface protein 1 (MSP1), a highly abundant ligand coating the merozoite surface in all species of malaria parasites, is essential for RBC invasion and considered a leading candidate for inclusion in a multiple-subunit vaccine against malaria. Our previous studies identified an interaction between the carboxyl-terminus of MSP1 and RBC band 3. Here, by employing phage display technology, we report a novel interaction between the amino-terminus of MSP1 and RBC glycophorin A (GPA). Mapping of the binding domains established a direct interaction between malaria MSP1 and human GPA within a region of MSP1 known to potently inhibit P falciparum invasion of human RBCs. Furthermore, a genetically modified mouse model lacking the GPA-band 3 complex in RBCs is completely resistant to malaria infection in vivo. These findings suggest an essential role of the MSP1-GPA-band 3 complex during the initial adhesion phase of malaria parasite invasion of RBCs. (Blood. 2015;125(17):2704-2711 IntroductionMalaria remains one of the most common and deadly parasitic diseases in the world. The World Health Organization estimates that 5% to 9% of the global population is infected by malaria annually, resulting in over 700 000 deaths.1 Children younger than 5 years are most vulnerable to Plasmodium falciparum, the most lethal species among 4 malaria parasites that commonly infect humans. Malaria also takes an enormous economic toll by impacting the economies of most endemic countries, particularly in sub-Saharan Africa. Historically, vaccines have been one of the most effective means of controlling infectious diseases. Accumulating evidence suggests that a malaria vaccine can be developed 2,3 ; however, most malaria vaccine candidate antigens have suffered limitations of low immunogenicity and efficacy. To date, no licensed vaccine exists for malaria despite the urgent global need.Clinical manifestation and mortality in malaria is directly associated with the blood stage of the parasite life cycle. The invasion process consists of multiple molecular events during which red blood cell (RBC) membrane proteins and merozoite-coat proteins are engaged in specific receptor-ligand interactions to form unique invasion pathways. 4,5 Continued interest in developing a multiantigen malaria vaccine has drawn much attention to parasite proteins localized on the surface and at the apical end of the merozoite as potential vaccine candidates. 4 Merozoite surface protein 1 (MSP1) is a major ligand coating the surface of merozoites in all species of malaria parasites 6 and is considered one of the leading candidates for inclusion in a multiplesubunit vaccine against...

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Section: Infection Of Band 3 and Protein 42 Null Mice By P Yoelii 17xlmentioning

confidence: 99%

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

Baldwin

Hanada

et al. 2015

Blood

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“…E64 irreversibly modifies the active site cysteine of the protease (35)(36)(37). By contrast, BDA-410, (C 26 H 32 N 2 O 5 S; MW, 484.61; half-life, ~400 minutes), is a novel orally active synthetic Leu-Leu peptidomimetic with a cyclopropenone group that strongly draws toward itself the hydrogen of the -SH residues of cysteines contained in the calpain molecule ( Figure 2A) (41). This leads to an intense electrostatic interaction between the resultant positively charged cyclopropenium ion and the -S -residue in calpain cysteines.…”

Section: Figurementioning

confidence: 99%

Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease

Trinchese¹,

Fà²,

Liu³

et al. 2008

J. Clin. Invest.

193

163

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Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD.

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“…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).…”

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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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BDA-410: A novel synthetic calpain inhibitor active against blood stage malaria

Cited by 25 publications

References 37 publications

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease

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

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