A kalihinol analog disrupts apicoplast function and vesicular trafficking in P. falciparum malaria.

We report the discovery of MED6-189, an analog of the kalihinol family of isocyanoterpene natural products that is effective against drug-sensitive and drug-resistant Plasmodium falciparum strains, blocking both asexual replication and sexual differentiation. In vivo studies using a humanized mouse model of malaria confirm strong efficacy of the compound in animals with no apparent hemolytic activity or toxicity. Complementary chemical, molecular, and genomics analyses revealed that MED6-189 targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. Its high potency, excellent therapeutic profile, and distinctive mode of action make MED6-189 an excellent addition to the antimalarial drug pipeline.

A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.

Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.

[The spectrum of prion pathology broadens: fatal familial insomnia]. / El espectro de la patología prion se amplía: el insomnio familiar fatal.

INTRODUCTION: The small group of prion diseases, caused by accumulation in the brain of an abnormal protein characterized by its aggregation and relative resistance to proteases (the PrPSc) in man is comprised of Creutzfeldt-Jacob disease (CJE), the Gerstmann-Straussler-Scheinker syndrome, kuru and the newest addition which is fatal familial insomnia (FFI). DEVELOPMENT: FFI is a hereditary condition with dominant autosomal transmission, characterized clinically by progressive insomnia, dysautonomy, changes in the circadian rhythm of hormone secretion, motor signs and slight to moderate deterioration of cognition. The usual age of onset is between 40 and 60 years, and the course of the illness lasts between 7 and 18 months. The histopathological changes, involving neurone loss and reactive gliosis, particularly affect the anteroventral and dorsomedial thalamic nuclei. These lesions lead to insomnia and to autonomic and endocrine disorders. To a lesser extent and degree, lesions are seen in other thalamic nuclei, the cerebral cortex, inferior olives and the cerebellum. FFI and some families with CJE have the same mutation of the codon 178 of the protein prion gene (gene PRNP) with substitution of aspartic acid by asparagine. Polymorphism of codon 129, which codifies methionine or valine determines the development of the clinical and neuropathological phenotype of FFI or CJE respectively. CONCLUSIONS: The description of FFI and the detection of PrPSe in familial cases of diffuse subcortical gliosis has indicated the possibility that there may be other familial or non-familial neurodegenerative diseases caused by prions.