Plasmodium RNA triphosphatase validation as antimalarial target.

Target-based approaches have traditionally been used in the search for new anti-infective molecules. Target selection process, a critical step in Drug Discovery, identifies targets that are essential to establish or maintain the infection, tractable to be susceptible for inhibition, selective towards their human ortholog and amenable for large scale purification and high throughput screening. The work presented herein validates the Plasmodium falciparum mRNA 5' triphosphatase (PfPRT1), the first enzymatic step to cap parasite nuclear mRNAs, as a candidate target for the development of new antimalarial compounds.

Lack of awareness of systemic lupus erythematosus and its consequences in a cohort of moderate and severe patients in Spain: The LupusVoice study.

Background And Objectives: Systemic lupus erythematosus (SLE) is an autoimmune condition that can highly impact patients' quality of life (QoL). However, there is a lack of knowledge about SLE, affecting the general population and health care professionals (HCPs) alike. This lack of knowledge has negative implications for patients and the healthcare system, worsening prognosis, negatively impacting QoL, and increasing healthcare utilization.

Use of belimumab in real-world in Spain: a scoping review about characteristics of SLE patients.

Background: Belimumab was the first biological drug approved for Systemic Lupus Erythematosus (SLE). There is not a review focusing on all real-life experience with belimumab to date that could help to describe how this drug behaves in the Spanish clinical setting.

Objective: To describe the characteristics of SLE patients treated with belimumab added to standard of care in real-clinical setting in Spain.

High-throughput microsphiltration to assess red blood cell deformability and screen for malaria transmission-blocking drugs.

The mechanical retention of rigid erythrocytes in the spleen is central in major hematological diseases such as hereditary spherocytosis, sickle-cell disease and malaria. Here, we describe the use of microsphiltration (microsphere filtration) to assess erythrocyte deformability in hundreds to thousands of samples in parallel, by filtering them through microsphere layers in 384-well plates adapted for the discovery of compounds that stiffen Plasmodium falciparum gametocytes, with the aim of interrupting malaria transmission. Compound-exposed gametocytes are loaded into microsphiltration plates, filtered and then transferred to imaging plates for analysis.

Functional screening of selective mitochondrial inhibitors of Plasmodium.

Phenotypic screening has produced most of the new chemical entities currently in clinical development for malaria, plus many lead compounds active against Plasmodium falciparum asexual stages. However, lack of knowledge about the mode of action of these compounds delays and may even hamper their future development. Identifying the mode of action of the inhibitors greatly helps to prioritise compounds for further development as novel antimalarials.

Submicroscopic Falciparum Malaria in Febrile Individuals in Urban and Rural Areas of Gabon.

AbstractCharacterization of the parasite reservoir is required to improve malaria control. Asymptomatic patients with subpatent parasitemia have been identified in Gabon, but the prevalence of such infections among febrile subjects is unclear. We assessed the prevalence of submicroscopic infections on an island (Port-Gentil), and in urban (Libreville), semiurban (Melen), and rural (Oyem) settings in Gabon.

A novel validated assay to support the discovery of new anti-malarial gametocytocidal agents.

Background: Drugs that kill or inhibit Plasmodium gametocytes in the human host could potentially synergize the impact of other chemotherapeutic interventions by blocking transmission. To develop such agents, reliable methods are needed to study the in vitro activity of compounds against gametocytes. This study describes a novel assay for characterizing the activity of anti-malarial drugs against the later stages of Plasmodium falciparum gametocyte development using real-time PCR (qPCR).

New molecular settings to support in vivo anti-malarial assays.

Background: Quantitative real-time PCR (qPCR) is now commonly used as a method to confirm diagnosis of malaria and to differentiate recrudescence from re-infection, especially in clinical trials and in reference laboratories where precise quantification is critical. Although anti-malarial drug discovery is based on in vivo murine efficacy models, use of molecular analysis has been limited. The aim of this study was to develop qPCR as a valid methodology to support pre-clinical anti-malarial models by using filter papers to maintain material for qPCR and to compare this with traditional methods.

Carbamoyl Triazoles, Known Serine Protease Inhibitors, Are a Potent New Class of Antimalarials.

Screening of the GSK corporate collection, some 1.9 million compounds, against Plasmodium falciparum (Pf), revealed almost 14000 active hits that are now known as the Tres Cantos Antimalarial Set (TCAMS). Followup work by Calderon et al.

Frequencies of dhfr/dhps multiple mutations and Plasmodium falciparum submicroscopic gametocyte carriage in Gabonese pregnant women following IPTp-SP implementation.

This study analyzed the relationship between intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) (IPTp-SP), the rate of multiple resistant parasites and of submicroscopic gametocyte carriage among pregnant women at the beginning of IPTp implementation in Gabon (2005) and six years after (2011). The detection of pfdhfr and pfdhps gene mutations was performed by PCR-RFLP in Plasmodium (P.) falciparum positive samples collected from pregnant women in 2005 and 2011.

Sub-microscopic gametocyte carriage in febrile children living in different areas of Gabon.

Background: Considering malaria prevalence declines in parts of sub-Saharan Africa, such as Gabon, identification of the human infectious reservoir is important for successful malaria control. Microscopic and sub-microscopic parasites contribute to malaria transmission. The aim of the present study was to evaluate the proportion of microscopic and sub-microscopic gametocyte carriers among febrile patients in two different areas of Gabon.

A new molecular approach for cidal vs static antimalarial determination by quantifying mRNA levels.

In order to maximise compliance, the future antimalarial treatment should ideally require just a single-dose administration. This, in turn, demands new fast-acting effective drugs. Currently, methods to measure the in vitro killing rate of antimalarials are based on parasite growth.

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

The resistance of malaria parasites to current anti-malarial drugs is an issue of major concern globally. Recently we identified a Plasmodium falciparum cell membrane aspartyl protease, which binds to erythrocyte band 3, and is involved in merozoite invasion. Here we report the complete primary structure of P.

Genetic conservation of the GIL blood group determining aquaporin 3 gene in African and Caucasian populations.

Background: The human GIL blood group is encoded by the aquaporin 3 (AQP3), a water-glycerol channel present in human red cell (RBC) membranes. So far no molecular investigation of this gene has been performed in an African population.

Study Design And Methods: To analyze the genetic variability of the AQP3 gene in African and European persons, all exons including the boundaries to introns and the promoter region were sequenced.

Limited genetic diversity of the Plasmodium falciparum aquaglyceroporin gene.

In Plasmodium falciparum small solutes like water, ammonium, glycerol and others are transported by a parasite-encoded channel into the parasite. The gene encoding this channel is termed P. falciparum aquaglyceroporin (PfAQP) and is a single-copy gene and highly homologous to other aquaporins from other protozoa.

Microwave-assisted ring opening of epoxides: a general route to the synthesis of 1-aminopropan-2-ols with anti malaria parasite activities.

A series of 1-aminopropan-2-ols were synthesized and evaluated against two strains of malaria, Plasmodium falciparum FCR3 (chloroquine-resistant) and 3D7 (chloroquine-sensitive). Microwave-assisted ring opening of epoxides (aryl and alkyl glycidyl ethers, glycidol, epichlorohydrin) with various amines without catalysts generated the desired library of beta-amino alcohols rapidly and efficiently. Most of the compounds showed micromolar potency against malaria, with seven of them having IC50 values between 1 and 10 microM against both Plasmodium falciparum strains.

Genes coding for tryptophan-rich proteins are transcribed throughout the asexual cycle of Plasmodium falciparum.

Multigene families are a common feature in Plasmodia spp. and constitute a substantial content of the parasite genome. Here, we analyse the structural organisation and sequence diversity of two further members of the Trp-rich multigene family of P.