scholarly journals The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

2015 ◽  
Vol 59 (10) ◽  
pp. 6203-6209 ◽  
Author(s):  
Thomas E. Kraft ◽  
Christopher Armstrong ◽  
Monique R. Heitmeier ◽  
Audrey R. Odom ◽  
Paul W. Hruz
Keyword(s):  
Glucose Transporter ◽  
Antimalarial Activity ◽  
Primary Source ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Malaria Parasites ◽  
Content Type ◽  
Growth And Survival ◽  
New Therapeutic Approaches ◽  
Mechanistic Basis

ABSTRACTMalaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance ofPlasmodiumspecies to existing therapies has increased the need for new therapeutic approaches. ThePlasmodiumglucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.

scholarly journals Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Hangjun Ke ◽  
Joanne M. Morrisey ◽  
Shiwei Qu ◽  
Oraphin Chantarasriwong ◽  
Michael W. Mather ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Morphological Changes ◽  
Biological Activities ◽  
Hek293 Cells ◽  
Therapeutic Window ◽  
Malaria Parasites ◽  
Content Type ◽  
Lead Compounds ◽  
Antimalarial Agents ◽  
Transport Chain

ABSTRACT Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

Antimalarial activity of sera from subjects taking HIV protease inhibitors

AIDS ◽  
2007 ◽  
Vol 21 (6) ◽  
pp. 763-765 ◽  
Author(s):  
Andrew M Redmond ◽  
Tina Skinner-Adams ◽  
Katherine T Andrews ◽  
Donald L Gardiner ◽  
John Ray ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Antimalarial Activity ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors

scholarly journals Using Lipoamidase as a Novel Probe To Interrogate the Importance of Lipoylation in Plasmodium falciparum

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Hugo Jhun ◽  
Maroya S. Walters ◽  
Sean T. Prigge
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Growth ◽  
Malaria Parasites ◽  
Subcellular Compartment ◽  
Content Type ◽  
Growth And Survival ◽  
Bacterial Enzyme ◽  
Parasite Survival ◽  
Key Aspects ◽  
Insight Into

ABSTRACT Lipoate is a redox active cofactor that is covalently bound to key enzymes of oxidative metabolism. Plasmodium falciparum is auxotrophic for lipoate during the intraerythrocytic stages, but it is not known whether lipoate attachment to protein is required or whether attachment is required in a specific subcellular compartment of the parasite. To address these questions, we used an enzyme called lipoamidase (Lpa) as a probe of lipoate metabolism. Lpa was first described in Enterococcus faecalis, and it specifically cleaves protein-bound lipoate, inactivating enzymes requiring this cofactor. Enzymatically active Lpa could be expressed in the cytosol of P. falciparum without any effect on protein lipoylation or parasite growth. Similarly, Lpa could be expressed in the apicoplast, and although protein lipoylation was reduced, parasite growth was not inhibited. By contrast, while an inactive mutant of Lpa could be expressed in the mitochondrion, the active enzyme could not. We designed an attenuated mutant of Lpa and found that this enzyme could be expressed in the parasite mitochondrion, but only in conjunction with a chemical bypass system. These studies suggest that acetyl-CoA production and a cryptic function of the H protein are both required for parasite survival. Our study validates Lpa as a novel probe of metabolism that can be used in other systems and provides new insight into key aspects of mitochondrial metabolism that are responsible for lipoate auxotrophy in malaria parasites. IMPORTANCE Lipoate is an essential cofactor for a small number of enzymes that are important for central metabolism. Malaria parasites require lipoate scavenged from the human host for growth and survival; however, it is not known why this cofactor is so important. To address this question, we designed a probe of lipoate activity based on the bacterial enzyme lipoamidase (Lpa). Expression of this probe in different subcellular locations allowed us to define the mitochondrion as the compartment housing essential lipoate metabolism. To gain further insight into the specific uses of lipoate in the mitochondrion, we designed a series of catalytically attenuated probes and employed the probes in conjunction with a chemical bypass system. These studies suggest that two lipoylated proteins are required for parasite survival. We were able to express Lpa with different catalytic abilities in different subcellular compartments and driven by different promoters, demonstrating the versatility of this tool and suggesting that it can be used as a probe of lipoate metabolism in other organisms.

scholarly journals Antimalarial Asexual Stage-Specific and Gametocytocidal Activities of HIV Protease Inhibitors

2009 ◽  
Vol 54 (3) ◽  
pp. 1334-1337 ◽  
Author(s):  
Christopher L. Peatey ◽  
Katherine T. Andrews ◽  
Nina Eickel ◽  
Timothy MacDonald ◽  
Alice S. Butterworth ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protease Inhibitors ◽  
Antimalarial Activity ◽  
Effective Concentration ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Asexual Stage ◽  
Gametocytocidal Activity

ABSTRACT The stage-specific antimalarial activities of a panel of antiretroviral protease inhibitors (PIs), including two nonpeptidic PIs (tipranavir and darunavir), were tested in vitro against Plasmodium falciparum. While darunavir demonstrated limited antimalarial activity (effective concentration [EC50], >50 μM), tipranavir was active at clinically relevant concentrations (EC50, 12 to 21 μM). Saquinavir, lopinavir, and tipranavir preferentially inhibited the growth of mature asexual-stage parasites (24 h postinvasion). While all of the PIs tested inhibited gametocytogenesis, tipranavir was the only one to exhibit gametocytocidal activity.

scholarly journals In VitroActivity of Antiretroviral Drugs against Plasmodium falciparum

2011 ◽  
Vol 55 (11) ◽  
pp. 5073-5077 ◽  
Author(s):  
Christian Nsanzabana ◽  
Philip J. Rosenthal
Keyword(s):  
Plasmodium Falciparum ◽  
Hiv Infection ◽  
Reverse Transcriptase ◽  
Inhibitory Concentration ◽  
Antimalarial Activity ◽  
Antiretroviral Drugs ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Reverse Transcriptase Inhibitors

ABSTRACTMalaria and HIV infection are both very common in many developing countries. With the increasing availability of therapy for HIV infection, it was of interest to determine whether antiretroviral drugs exert antimalarial effects. We therefore tested thein vitroactivity of 19 antiretroviral drugs against the W2 and 3D7 strains ofPlasmodium falciparumat concentrations up to 50 μM. None of 5 tested nucleoside reverse transcriptase inhibitors demonstrated activity. Two nonnucleoside reverse transcriptase inhibitors, efavirenz (mean 50% inhibitory concentration [IC50] of 22 to 30 μM against the two strains) and etravirine (3.1 to 3.4 μM), were active; nevirapine was not active. Also active were the fusion inhibitor enfuvirtide (6.2 to 7.9 μM) and the entry inhibitor maraviroc (15 to 21 μM). Raltegravir was not active. However, for all active drugs mentioned above, the IC50s were considerably greater than the concentrations achieved with standard dosing. The effects most likely to be clinically relevant were with HIV protease inhibitors. Of the tested compounds, activity was seen with lopinavir (2.7 to 2.9 μM), atazanavir (3.3 to 13.0 μM), saquinavir (5.0 to 12.1 μM), nelfinavir (6.5 to 12.1 μM), ritonavir (9.5 to 10.9 μM), tipranavir (15.5 to 22.3 μM), and amprenavir (28.1 to 40.8) but not darunavir. Lopinavir was active at levels well below those achieved with standard dosing of coformulated lopinavir-ritonavir. Lopinavir also demonstrated modest synergy with the antimalarial lumefantrine (mean fractional inhibitory concentration index of 0.66 for W2 and 0.53 for 3D7). Prior data showed that lopinavir-ritonavir also extends the pharmacokinetic exposure of lumefantrine. Thus, when used to treat HIV infection, lopinavir-ritonavir may have clinically relevant antimalarial activity and also enhance the activity of antimalarials.

Determining and Overcoming Resistance to HIV Protease Inhibitors

2004 ◽  
Vol 4 (2) ◽  
pp. 137-152 ◽  
Author(s):  
Jana Prejdova ◽  
Milan Soucek ◽  
Jan Konvalinka
Keyword(s):  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors

A QSAR Study of HIV Protease Inhibitors Using Theoretical Descriptors

2010 ◽  
Vol 6 (4) ◽  
pp. 269-282 ◽  
Author(s):  
Subhash C. Basak ◽  
Denise Mills ◽  
Rajni Garg ◽  
Barun Bhhatarai
Keyword(s):  
Protease Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Qsar Study

The 2016 Police and Crime Commissioner elections

2017 ◽  
Vol 16 (2) ◽  
pp. 41-54 ◽  
Author(s):  
Peter Joyce
Keyword(s):  
Public Awareness ◽  
Primary Source ◽  
Source Material ◽  
Content Type ◽  
The Public ◽  
The Social ◽  
Key Issues ◽  
The Subject ◽  
The Government

Purpose The purpose of this paper is to analyse the 2016 elections for Police and Crime Commissioners (PCCs) and to compare them with those that took place in 2012. It seeks to evaluate the background of the candidates who stood for office in 2016, the policies that they put forward, the results of the contests and the implications of the 2016 experience for future PCC elections. Design/methodology/approach This paper is based around several key themes – the profile of candidates who stood for election, preparations conducted prior to the contests taking place, the election campaign and issues raised during the contests, the results and the profile of elected candidates. The paper is based upon documentary research, making particular use of primary source material. Findings The research establishes that affiliation to a political party became the main route for successful candidates in 2016 and that local issues related to low-level criminality will dominate the future policing agenda. It establishes that although turnout was higher than in 2012, it remains low and that further consideration needs to be devoted to initiatives to address this for future PCC election contests. Research limitations/implications The research focusses on the 2016 elections and identifies a number of key issues that emerged during the campaign affecting the conduct of the contests which have a bearing on future PCC elections. It treats these elections as a bespoke topic and does not seek to place them within the broader context of the development of the office of PCC. Practical implications The research suggests that in order to boost voter participation in future PCC election contests, PCCs need to consider further means to advertise the importance of the role they perform and that the government should play a larger financial role in funding publicity for these elections and consider changing the method of election. Social implications The rationale for introducing PCCs was to empower the public in each police force area. However, issues that include the enhanced importance of political affiliation as a criteria for election in 2016 and the social unrepresentative nature of those who stood for election and those who secured election to this office in these contests coupled with shortcomings related to public awareness of both the role of PCCs and the timing of election contests threaten to undermine this objective. Originality/value The extensive use of primary source material ensures that the subject matter is original and its interpretation is informed by an academic perspective.

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