Biomedical subjects

Colin Berry

Publications and source records attributed to Colin Berry.

At least 37 records · Page 2Linked to original sources

PubMed2005

The activity and inhibition of the food vacuole plasmepsin from the rodent malaria parasite Plasmodium chabaudi.

The rodent malaria parasite Plasmodium chabaudi encodes one food vacuole plasmepsin-the aspartic proteinases important in haemoglobin degradation. A recombinant form of this enzyme was found to cleave a variety of peptide substrates and was susceptible to a selection of naturally occurring and synthetic inhibitors, displaying an inhibition profile distinct from that of aspartic proteinases from other malaria parasites. In addition, inhibitors of HIV proteinase that kill P. chabaudi in vivo were also inhibitors of this new plasmepsin. P. chabaudi is a widely used model for human malaria species and, therefore, the characterisation of this plasmepsin is an important contribution towards understanding its biology.

Amino Acid Sequence↗

PubMed2005

Analogues of thiolactomycin as potential antimalarial agents.

Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗

PubMed2005

Antimalarial effects of HIV proteinase inhibitors: common compounds but structurally distinct enzymes.

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Animals↗

PubMed2005

Ximelagatran compared with warfarin for the prevention of systemic embolism and stroke. An imputed placebo analysis.

The active control trials, SPORTIF III and SPORTIF V, compared the direct thrombin inhibitor ximelagatran to warfarin, where each was given as a treatment to prevent systemic embolism and stroke in patients with atrial fibrillation. Because warfarin has previously been compared to placebo in similar patients and ximelagatran has now been compared to warfarin, an indirect comparison between ximelagatran and placebo is possible (imputed placebo analysis). In this analysis, ximelagatran reduces the risk of stroke and systemic embolism by 66% (hazard ratio 0.338; 95% confidence interval [CI] 0.204-0.560). Ximelagatran preserves 102% (95% CI 72-132%) of the benefit of warfarin. Based on these data, ximelagatran may be an effective alternative to warfarin for the prevention of stroke and systemic embolism in high-risk patients with atrial fibrillation.

Aged↗

PubMed2005

dUTPase as a platform for antimalarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors.

Pyrimidine metabolism is a major route for therapeutic intervention against malaria. Here we report inhibition and structural studies on the deoxyuridine nucleotidohydrolase from the malaria parasite Plasmodium falciparum (PfdUTPase). We have identified a series of triphenylmethane derivatives of deoxyuridine with antimalarial activity in vitro which inhibit specifically the Plasmodium dUTPase versus the human enzyme. A 2.4 Angstrom crystal structure of PfdUTPase in complex with one of these inhibitors reveals an atypical trimeric enzyme in which the triphenylmethane derivative can be seen to select for PfdUTPase by way of interactions between the trityl group and the side chains of residues Phe46 and Ile117. Immunofluorescence microscopy studies of parasitized red blood cells reveal that enzyme concentrations are highest during the trophozoite/schizont stages, suggesting that PfdUTPase has a major role in DNA replication. Taken together the data show that PfdUTPase may be considered as an antimalarial drug target.

Amino Acid Sequence↗

PubMed2004

Staphylococcus aureus DNA ligase: characterization of its kinetics of catalysis and development of a high-throughput screening compatible chemiluminescent hybridization protection assay.

DNA ligases are key enzymes involved in the repair and replication of DNA. Prokaryotic DNA ligases uniquely use NAD+ as the adenylate donor during catalysis, whereas eukaryotic enzymes use ATP. This difference in substrate specificity makes the bacterial enzymes potential targets for therapeutic intervention. We have developed a homogeneous chemiluminescence-based hybridization protection assay for Staphylococcus aureus DNA ligase that uses novel acridinium ester technology and demonstrate that it is an alternative to the commonly used radiometric assays for ligases. The assay has been used to determine a number of kinetic constants for S. aureus DNA ligase catalysis. These included the K(m) values for NAD+ (2.75+/-0.1 microM) and the acridinium-ester-labelled DNA substrate (2.5+/-0.2 nM). A study of the pH-dependencies of kcat, K(m) and kcat/K(m) has revealed values of kinetically influential ionizations within the enzyme-substrate complexes (kcat) and free enzyme (kcat/K(m)). In each case, the curves were shown to be composed of one kinetically influential ionization, for k(cat), pK(a)=6.6+/-0.1 and kcat/K(m), pK(a)=7.1+/-0.1. Inhibition characteristics of the enzyme against two Escherichia coli DNA ligase inhibitors have also been determined with IC50 values for these being 3.30+/-0.86 microM for doxorubicin and 1.40+/-0.07 microM for chloroquine diphosphate. The assay has also been successfully miniaturized to a sufficiently low volume to allow it to be utilized in a high-throughput screen (384-well format; 20 microl reaction volume), enabling the assay to be used in screening campaigns against libraries of compounds to discover leads for further drug development.

Acridines↗

PubMed2004

Comparison of femoral bleeding complications after coronary angiography versus percutaneous coronary intervention.

Vascular complications arising after coronary angiography (CA) and percutaneous coronary intervention (PCI) may be under-reported. Access site complications were studied after consecutive CA and PCI in the investigators' center (an urban university hospital) from October to December 2002. Three hundred eleven consecutive procedures (237 CA studies and 74 PCIs) were included, of which 309 (99%) involved femoral arterial access. Seventy percent of all arterial punctures were closed by manual pressure, 28% by C-pressure clamps, and 2% with closure devices. Femoral hematomas occurred in 22% and 41% of CA studies and PCIs, respectively. Hematoma >5 cm occurred in 6% and 11% of CA studies and PCIs, respectively. Nineteen patients (23%) with access site complications had prolonged hospital admission. Increased body mass index and hematoma development within the catheter laboratory were predictors of prolonged admission.

Age Distribution↗

PubMed2004

Analogues of thiolactomycin as potential anti-malarial and anti-trypanosomal agents.

A series of analogues of the naturally occurring antibiotic thiolactomycin (TLM) have been synthesised and evaluated for their ability to inhibit the growth of the malaria parasite, Plasmodium falciparum. Thiolactomycin is an inhibitor of Type II fatty acid synthase which is found in plants and most prokaryotes, but not an inhibitor of Type I fatty acid synthase in mammals. A number of the analogues showed inhibition equal to or greater than TLM. The introduction of hydrophobic alkyl groups at the C3 and C5 positions of the thiolactone ring lead to increased inhibition, the best showing a fourteenfold increase in activity over TLM. In addition, some of the analogues showed activity when assayed against the parasitic protozoa, Trypanosoma cruzi and Trypanosoma brucei.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗

PubMed2004