Design and tests of prospective property predictions for novel antimalarial 2-aminopropylaminoquinolones.

There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure-activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture.

A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission.

To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC of 160 pM in a PfPKG kinase assay and inhibits P.

A high-throughput fluorescence-based assay for Plasmodium dihydroorotate dehydrogenase inhibitor screening.

Plasmodium dihydroorotate dehydrogenase (DHODH) is a mitochondrial membrane-associated flavoenzyme that catalyzes the rate-limiting step of de novo pyrimidine biosynthesis. DHODH is a validated target for malaria, and DSM265, a potent inhibitor, is currently in clinical trials. The enzyme catalyzes the oxidation of dihydroorotate to orotate using flavin mononucleotide (FMN) as cofactor in the first half of the reaction.

ALG-2 interacting protein AIP1: a novel link between D1 and D3 signalling.

Dopamine signalling is a critically important process in the human brain that controls mood, cognition and motor activity. In order to gain detailed insight into this signalling pathway at the molecular level, we carried out yeast two-hybrid screens with D1-like (D1, D5) and D2-like (D2, D3, D4) dopamine receptors and identified 11 dopamine receptor interacting proteins (DRIPs). Using the C-terminal domain of D1 receptor as bait, we identified AIP1 (ALG-2 interacting protein 1), a known modulator of caspase-dependent and caspase-independent cell death, including neuronal cell death, that is also part of the endosomal transport system.

Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation.

Mutations in the human methyl-CpG-binding protein gene MECP2 cause the neurological disorder Rett syndrome and some cases of X-linked mental retardation (XLMR). We report that MeCP2 interacts with ATRX, a SWI2/SNF2 DNA helicase/ATPase that is mutated in ATRX syndrome (alpha-thalassemia/mental retardation, X-linked). MeCP2 can recruit the helicase domain of ATRX to heterochromatic foci in living mouse cells in a DNA methylation-dependent manner.

Regulation of mature T lymphocyte proliferation and differentiation by Par-4.

The genetic inactivation of the atypical protein kinase C (aPKC) inhibitor, Par-4, gives rise to increased NF-kappaB activation and decreased stimulation of JNK in embryo fibroblasts. Here we have characterized the immunological phenotype of the Par-4(-/-) mice and found that the loss of this gene leads to an increased proliferative response of peripheral T cells when challenged through the TCR. This is accompanied by a higher increase in cell cycle entry and inhibition of apoptosis, with enhanced IL-2 secretion but normal CD25 synthesis.

Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38.

The Par4 gene was first identified in prostate cells undergoing apoptosis after androgen withdrawal. PAR4 was subsequently shown to interact with, and inhibit, atypical protein kinase C isoforms, functioning as a negative regulator of the NF-kappaB pathway. This may explain its pro-apoptotic function in overexpression experiments.

Functional analysis of the Saccharomyces cerevisiae DUP240 multigene family reveals membrane-associated proteins that are not essential for cell viability.

The DUP240 gene family of Saccharomyces cerevisiae is composed of 10 members. They encode proteins of about 240 amino acids which contain two predicted transmembrane domains. Database searches identified only one homologue in the closely related species Saccharomyces bayanus, indicating that the DUP240 genes encode proteins specific to Saccharomyces sensu stricto.