Characterization of the Plasmodium falciparum M17 leucyl aminopeptidase. A protease involved in amino acid regulation with potential for antimalarial drug development

Amino acids generated from the catabolism of hemoglobin by intra-erythrocytic malaria parasites are not only essential for protein synthesis but also function in maintaining an osmotically stable environment, and creating a gradient by which amino acids that are rare or not present in hemoglobin are drawn into the parasite from host serum. We have proposed that a Plasmodium falciparum M17 leucyl aminopeptidase (PfLAP) generates and regulates the internal pool of free amino acids and therefore represents a target for novel antimalarial drugs. This enzyme has been expressed in insect cells as a functional 320-kDa homo-hexamer that is optimally active at neutral or alkaline pH, is dependent on metal ions for activity, and exhibits a substrate preference for N-terminally exposed hydrophobic amino acids, particularly leucine. PfLAP is produced by all stages in the intra-erythrocytic developmental cycle of malaria but was most highly expressed by trophozoites, a stage at which hemoglobin degradation and parasite protein synthesis are elevated. The enzyme was located by immunohistochemical methods and by transfecting malaria cells with a PfLAP-green fluorescent protein construct, to the cytosolic compartment of the cell at all developmental stages, including segregated merozoites. Amino acid dipeptide analogs, such as bestatin and its derivatives, are potent inhibitors of the protease and also block the growth of P. falciparum malaria parasites in culture. This study provides a biochemical basis for the antimalarial activity of aminopeptidase inhibitors. Availability of functionally active recombinant PfLAP, coupled with a simple enzymatic readout, will aid medicinal chemistry and/or high throughput approaches for the future design/discovery of new antimalarial drugs

US Central Command and liberal imperial reach: ‘Shaping the Central Region for the 21st Century’

For over 30 years, the grand strategy of one of the most important commands in the US military, Central Command (CENTCOM), has consistently held fast to a commitment to neoliberal capitalism and an ostensibly free-market global economy. Any accrued national or global economic benefits are impossible to chart, of course, and so CENTCOM's securitization discourse relies upon vaguer, yet promissory logics about keeping the global economy open'. My aim in this paper is to show how the story of CENTCOM's mission is crucial to understanding how US military interventionism works today through a discursive geoeconomic imagination that is vague yet persuasive in its universalist dimensions. In a period marked by globalisation and new forms of capitalist accumulation, CENTCOM's mission has nevertheless habitually involved fashioning itself in a neoliberal world policeman' role, and to that end has employed a strategy that can be best described as one of geoeconomic deterrence'. The paper outlines the entwined military and economic security logics of this strategy, which have resulted in the Middle East and Central Asia being repeatedly conditioned as requiring forms of corrective military interventionism. Since its establishment in 1983, CENTCOM's strategy papers, mission statements and annual reports to Congress have collectively scripted practices of intervention and deterrence that rely upon dominant registers of military and economic risk. In critically considering CENTCOM's mission, the paper shows how the command's initiation fundamentally changed US foreign policy by solidifying the Carter Doctrine and subsequently committing to the geoeconomic shaping of the most energy-rich region on earth.peer-reviewe