Identification of mCMQ069, a novel antimalarial with potential for a single-dose cure and/or 28-day chemoprevention.

In efforts towards eliminating malaria, a discovery program was initiated to identify a novel antimalarial using KAF156 as a starting point. Following the most recent TCP/TPP guidelines, we have identified mCMQ069 with a predicted single oral dose for treatment (∼40-106 mg) and one-month chemoprevention (∼96-216 mg). We have improved unbound MPC and predicted human clearance by 18-fold and 10-fold respectively when compared to KAF156.

A Phase 2a randomized, single-center, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of oral iOWH032 against cholera diarrhea in a controlled human infection model.

Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera.

Sensitive and semiquantitative detection of soil-transmitted helminth infection in stool using a recombinase polymerase amplification-based assay.

Background: Soil-transmitted helminths (STHs) are parasitic nematodes that inhabit the human intestine. They affect more than 1.5 billion people worldwide, causing physical and cognitive impairment in children.

Spontaneous Selection of Drug Resistance in a Calf Model of Infection.

The intestinal protozoan is a leading cause of diarrheal disease and mortality in young children. There is currently no fully effective treatment for cryptosporidiosis, which has stimulated interest in anticryptosporidial development over the last ∼10 years, with numerous lead compounds identified, including several tRNA synthetase inhibitors. Here, we report the results of a dairy calf efficacy trial of the methionyl-tRNA ( MetRS [MetRS]) synthetase inhibitor 2093 and the spontaneous emergence of drug resistance.

Validation of the Micronutrient and Environmental Enteric Dysfunction Assessment Tool and evaluation of biomarker risk factors for growth faltering and vaccine failure in young Malian children.

Environmental enteric dysfunction (EED) is an intestinal disorder common among children in low-resource settings and is associated with increased risk of growth stunting, cognitive deficits, and reduced oral vaccine immunogenicity. The Micronutrient and EED Assessment Tool (MEEDAT) is a multiplexed immunoassay that measures biomarkers previously associated with child growth faltering and/or oral vaccine immunogenicity: intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), insulin-like growth factor 1 (IGF-1), and fibroblast growth factor 21 (FGF21). MEEDAT also measures systemic inflammation (α1-acid glycoprotein, C-reactive protein), ferritin, soluble transferrin receptor, retinol binding protein 4, thyroglobulin, and Plasmodium falciparum antigenemia (histidine-rich protein 2).

Bumped Kinase Inhibitors as therapy for apicomplexan parasitic diseases: lessons learned.

Bumped Kinase Inhibitors, targeting Calcium-dependent Protein Kinase 1 in apicomplexan parasites with a glycine gatekeeper, are promising new therapeutics for apicomplexan diseases. Here we will review advances, as well as challenges and lessons learned regarding efficacy, safety, and pharmacology that have shaped our selection of pre-clinical candidates.

Morbidity, mortality, and long-term consequences associated with diarrhoea from Cryptosporidium infection in children younger than 5 years: a meta-analyses study.

Background: The protozoan Cryptosporidium is a leading cause of diarrhoea morbidity and mortality in children younger than 5 years. However, the true global burden of Cryptosporidium infection in children younger than 5 years might have been underestimated in previous quantifications because it only took account of the acute effects of diarrhoea. We aimed to demonstrate whether there is a causal relation between Cryptosporidium and childhood growth and, if so, to quantify the associated additional burden.

Pediatric cryptosporidiosis: An evaluation of health care and societal costs in Peru, Bangladesh and Kenya.

Cryptosporidium is a leading cause of pediatric diarrhea in resource-limited settings; yet, few studies report the health care costs or societal impacts of this protozoan parasite. Our study examined direct and indirect costs associated with symptomatic cryptosporidiosis in infants younger than 12 months in Kenya, Peru and Bangladesh. Inputs to the economic burden model, such as disease incidence, population size, health care seeking behaviour, hospital costs, travel costs, were extracted from peer-reviewed literature, government documents, and internationally validated statistical tools for each country.

Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea.

Racecadotril (acetorphan) is a neutral endopeptidase (NEP) inhibitor with known antidiarrheal activity in animals and humans; however, in humans, it suffers from shortcomings that might be improved with newer drugs in this class that have progressed to the clinic for nonenteric disease indications. To identify potentially superior NEP inhibitors with immediate clinical utility for diarrhea treatment, we compared their efficacy and pharmacologic properties in a rat intestinal hypersecretion model. Racecadotril and seven other clinical-stage inhibitors of NEP were obtained or synthesized.

SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of CDPK1.

We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from . The current work, through structure-activity relationship studies, led to the discovery of compounds ( and ) with improved characteristics over the starting inhibitor in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds and were further demonstrated to be more effective than in a mouse infection model and markedly reduced the amount of in the brain, spleen, and peritoneal fluid, and given at 20 mg/kg eliminated from the peritoneal fluid.

Carbon-14 labelled tribendimidine, a broad-spectrum anthelmintic drug.

The preparation of [(14) C]tribendimidine, a broad-spectrum anthelmintic agent related to amidantel, and its use during excretion and metabolism studies in the rat are described in this paper.

Developing novel antisecretory drugs to treat infectious diarrhea.

Diarrhea, a disease of poverty and poor sanitation, kills an estimated two million children each year. Oral rehydration therapy is a very simple and inexpensive treatment that has significantly reduced mortality from secretory diarrhea caused by rotavirus, cholera and enterotoxigenic Escherichia coli. The efficacy and adoption of oral rehydration therapy would be enhanced by a drug that reduces fluid loss associated with these diseases and alleviates disease symptoms.

A brief history of the coronin family.

What I'd like to do in this chapter is to share with you my recollections from the earliest days of coronin research and then to provide an overview of the still-developing story of this fascinating family of proteins.

Localization of the transmembrane proteoglycan syndecan-4 and its regulatory kinases in costameres of rat cardiomyocytes: a deconvolution microscopic study.

Syndecan-4 (syn-4), a transmembrane heparan sulfate-containing proteoglycan, is unique among the four members of the syndecan family in its specific cellular localization to complex cytoskeletal adhesion sites, i.e., focal adhesions.

Genetic and morphological evidence for two parallel pathways of cell-cycle-coupled cytokinesis in Dictyostelium.

Myosin-II-null cells of Dictyostelium discoideum cannot divide in suspension, consistent with the dogma that myosin II drives constriction of the cleavage furrow and, consequently, cytokinesis (cytokinesis A). Nonetheless, when grown on substrates, these cells exhibit efficient, cell-cycle-coupled division, suggesting that they possess a novel, myosin-II-independent, adhesion-dependent method of cytokinesis (cytokinesis B). Here we show that double mutants lacking myosin II and either AmiA or coronin, both of which are implicated in cytokinesis B, are incapable of cell-cycle-coupled cytokinesis.

Microtubule organization and the effects of GFP-tubulin expression in dictyostelium discoideum.

We have labeled microtubules in living Dictyostelium amoebae by incorporation of a GFP-alpha-tubulin fusion protein. The GFP-alpha-tubulin incorporates into microtubules and, as reported by others [Neujahr et al., 1998], the labeled microtubules are highly motile.

Cloning and characterization of the Dictyostelium discoideum cycloartenol synthase cDNA.

Cycloartenol synthase converts oxidosqualene to cycloartenol, the first carbocyclic intermediate en route to sterols in plants and many protists. Presented here is the first cycloartenol synthase gene identified from a protist, the cellular slime mold Dictyostelium discoideum. The cDNA encodes an 81-kDa predicted protein 50-52% identical to known higher plant cycloartenol synthases and 40-49% identical to known lanosterol synthases from fungi and mammals.

Reconstitution of membrane transport powered by a novel dimeric kinesin motor of the Unc104/KIF1A family purified from Dictyostelium.

Motor-powered movement along microtubule tracks is important for membrane organization and trafficking. However, the molecular basis for membrane transport is poorly understood, in part because of the difficulty in reconstituting this process from purified components. Using video microscopic observation of organelle transport in vitro as an assay, we have purified two polypeptides (245 and 170 kD) from Dictyostelium extracts that independently reconstitute plus-end-directed membrane movement at in vivo velocities.

Listeria monocytogenes exploits normal host cell processes to spread from cell to cell.

The bacterial pathogen, Listeria monocytogenes, grows in the cytoplasm of host cells and spreads intercellularly using a form of actin-based motility mediated by the bacterial protein ActA. Tightly adherent monolayers of MDCK cells that constitutively express GFP-actin were infected with L. monocytogenes, and intercellular spread of bacteria was observed by video microscopy.

The coronin family of actin-associated proteins.

Coronin was first isolated from Dictyostelium, but similar proteins have been identified in many species and individual cell types. The coronin-like protein in yeast promotes actin polymerization and also interacts with microtubules. Dictyostelium mutants lacking coronin are impaired in cytokinesis and all actin-mediated processes.

Architectural dynamics of F-actin in eupodia suggests their role in invasive locomotion in Dictyostelium.

Eupodia are F-actin-containing cortical structures similar to vertebrate podosomes or invadopodia found in metastatic cells. Eupodia are rich in alpha-actinin and myosin IB/D, but not a Dictyostelium homologue of talin. In the present study, we localized other actin-binding proteins, ABP120, cofilin, coronin, and fimbrin, in the eupodia and examined the three-dimensional organization of their F-actin system by confocal microscopy and transmission electron microscopy.

Architectural dynamics and gene replacement of coronin suggest its role in cytokinesis.

Coronin is a ubiquitous actin-binding protein representing a member of proteins portraying a WD-repeat sequence, including the beta-subunits of trimeric G-proteins. Coronin has been suggested to participate in multiple, actin-based physiological activities such as cell movement and cell division. Although the slow growth of coronin deletion mutants has been attributed to a defect in the fluid-phase uptake of nutrients, the exact role of coronin in cytoskeletal organization has not been elucidated.

A developmentally regulated kinesin-related motor protein from Dictyostelium discoideum.

The cellular slime mold Dictyostelium discoideum is an attractive system for studying the roles of microtubule-based motility in cell development and differentiation. In this work, we report the first molecular characterization of kinesin-related proteins (KRPs) in Dictyostelium. A PCR-based strategy was used to isolate DNA fragments encoding six KRPs, several of which are induced during the developmental program that is initiated by starvation.