Identification of Specific and Nonspecific Inhibitors of Bacillus anthracis Type III Pantothenate Kinase (PanK).

Antibiotics with novel mechanisms of action are desperately needed to combat the increasing rates of multidrug-resistant infections. Bacterial pantothenate kinase (PanK) has emerged as a target of interest to cut off the biosynthesis of coenzyme A. Herein we report the results of an in vitro high-throughput screen of over 10 000 small molecules against Bacillus anthracis PanK, as well as a follow-up screen of hits against PanK isolated from Pseudomonas aeruginosa and Burkholderia cenocepacia.

Screening and Development of New Inhibitors of FtsZ from M. Tuberculosis.

A variety of commercial analogs and a newer series of Sulindac derivatives were screened for inhibition of M. tuberculosis (Mtb) in vitro and specifically as inhibitors of the essential mycobacterial tubulin homolog, FtsZ. Due to the ease of preparing diverse analogs and a favorable in vivo pharmacokinetic and toxicity profile of a representative analog, the Sulindac scaffold may be useful for further development against Mtb with respect to in vitro bacterial growth inhibition and selective activity for Mtb FtsZ versus mammalian tubulin.

Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells.

The enzyme cytochrome c oxidase (CcO) or complex IV (EC 1.9.3.

Inhibition of pro-HGF activation by SRI31215, a novel approach to block oncogenic HGF/MET signaling.

The binding of hepatocyte growth factor (HGF) to its receptor MET activates a signaling cascade that promotes cell survival, proliferation, cell scattering, migration and invasion of malignant cells. HGF is secreted by cancer cells or by tumor-associated fibroblasts as pro-HGF, an inactive precursor. A key step in the regulation of HGF/MET signaling is proteolytic processing of pro-HGF to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA).

Design and Synthesis of Nonpeptide Inhibitors of Hepatocyte Growth Factor Activation.

In this letter we report first nonpeptide inhibitors of hepatocyte growth factor (HGF) activation. These compounds inhibit the three proteases (matriptase, hepsin, and HGF activator) required for HGF maturation. We show that 6, 8a, 8b, and 8d block activation of fibroblast-derived pro-HGF, thus preventing fibroblast-induced scattering of DU145 prostate cancer cells.

Discovery of a novel inhibitor of kinesin-like protein KIFC1.

Historically, drugs used in the treatment of cancers also tend to cause damage to healthy cells while affecting cancer cells. Therefore, the identification of novel agents that act specifically against cancer cells remains a high priority in the search for new therapies. In contrast with normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis.

Unique functional and structural properties of the LRRK2 protein ATP-binding pocket.

Pathogenic mutations in the LRRK2 gene can cause late-onset Parkinson disease. The most common mutation, G2019S, resides in the kinase domain and enhances activity. LRRK2 possesses the unique property of cis-autophosphorylation of its own GTPase domain.

A novel quinoline derivative that inhibits mycobacterial FtsZ.

High throughput phenotypic screening of large commercially available libraries through two NIH programs has produced thousands of potentially interesting hits for further development as antitubercular agents. Unfortunately, these screens do not supply target information, and further follow up target identification is required to allow optimal rational design and development of highly active and selective clinical candidates. Cheminformatic analysis of the quinoline and quinazoline hits from these HTS screens suggested a hypothesis that certain compounds in these two classes may target the mycobacterial tubulin homolog, FtsZ.

Novel pyridopyrazine and pyrimidothiazine derivatives as FtsZ inhibitors.

A series of pyridopyrazine and pyrimidothiazine derivatives have been synthesized and their activity against FtsZ from Mycobacterium tuberculosis (Mtb) and in vitro antibacterial activity against Mtb H(37)Ra and Mtb H(37)Rv are reported. Certain analogs described herein showed moderate to good inhibitory activity.

Family, friends, and faith: how organ donor families heal.

Context: Understanding how organ donors' families recover from their grief can help organ procurement organizations improve consent rates and increase the number of deceased donor organs available for transplant.

Objective: To determine what helps the loved ones of deceased organ donors heal from their grief and loss, and to better understand families' needs during the consent process as a way of improving overall consent rates for organ donation.

Design, Setting, And Participants: Written survey of all organ and tissue donors' families in the San Diego and Imperial County (California) service area during 2006 and 2007.

Structure-based virtual screening against SARS-3CL(pro) to identify novel non-peptidic hits.

Severe acute respiratory syndrome is a highly infectious upper respiratory tract disease caused by SARS-CoV, a previously unidentified human coronavirus. SARS-3CL(pro) is a viral cysteine protease critical to the pathogen's life cycle and hence a therapeutic target of importance. The recently elucidated crystal structures of this enzyme provide an opportunity for the discovery of inhibitors through rational drug design.

Metoclopramide does not influence the frequency of propofol-induced spontaneous movements.

Study Objective: To evaluate the effects of metoclopramide on the frequency and severity of propofol-induced movements.

Design: Randomized, double blind, placebo-controlled trial.

Setting: Veterans Administration Medical Center.

A novel inhibitor of Mycobacterium tuberculosis pantothenate synthetase.

Pantothenate synthetase (PS; EC 6.3.2.

Genome evolution in the genus Sorghum (Poaceae).

Background And Aims: The roles of variation in DNA content in plant evolution and adaptation remain a major biological enigma. Chromosome number and 2C DNA content were determined for 21 of the 25 species of the genus Sorghum and analysed from a phylogenetic perspective.

Methods: DNA content was determined by flow cytometry.

Structure of Mycobacterium tuberculosis FtsZ reveals unexpected, G protein-like conformational switches.

We report three crystal structures of the Mycobacterium tuberculosis cell division protein FtsZ, as the citrate, GDP, and GTPgammaS complexes, determined at 1.89, 2.60, and 2.

Cloning, expression, and characterization of Mycobacterium tuberculosis dihydrofolate reductase.

The gene for dihydrofolate reductase of Mycobacterium tuberculosis was amplified by polymerase chain reaction (PCR) from M. tuberculosis H37Rv strain genomic DNA. The protein was expressed in inclusion bodies in high yield in Escherichia coli under the control of the T7 promoter.

Masquerading as self? Endoparasitic Strepsiptera (Insecta) enclose themselves in host-derived epidermal bag.

We report here the case of a metazoan parasite, a strepsipteran, that manipulates host epidermal tissue and wraps itself within it; which probably camouflages the endoparasite and is recognized as "self" by the host. This mechanism is one of immune avoidance among parasitoid insects. The host-derived epidermal "bag" might have enabled Strepsiptera to radiate to disparate hosts compared with the relatively few taxa (596 species) described so far.

Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 a and 1.05 a resolution.

The crystal structures of two human dihydrofolate reductase (hDHFR) ternary complexes, each with bound NADPH cofactor and a lipophilic antifolate inhibitor, have been determined at atomic resolution. The potent inhibitors 6-([5-quinolylamino]methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9439) and (Z)-6-(2-[2,5-dimethoxyphenyl]ethen-1-yl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9662) were developed at Southern Research Institute against Toxoplasma gondii DHFR-thymidylate synthase. The 5-deazapteridine ring of each inhibitor adopts an unusual puckered conformation that enables the formation of identical contacts in the active site.

2-Alkoxycarbonylaminopyridines: inhibitors of Mycobacterium tuberculosis FtsZ.

Compounds originally designed as putative tubulin inhibitors were tested as antitubercular agents for inhibition of the Mycobacterium tuberculosis analogue of tubulin, FtsZ. Initial screening of 200 2-alkoxycarbonylpyridines found several that inhibited M. tuberculosis growth.