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PubMed2002

Determining antibiotic resistance in Helicobacter pylori.

Resistance development is a significant clinical problem in Helicobacter pylori and represents the major cause of treatment failure. Today the problem is most focused on the macrolide clarithromycin that is an essential component of the H. pylori treatment. Traditional methods for resistance determination, e.g., disc diffusion tests or E-tests, could in the next 5 years be replaced by DNA-based methods. The most commonly used molecular methods available today are not used in the daily routine work. Rapid and reliable DNA-based methods for prediction of antimicrobial resistance phenotype are currently available within research. As fabrication costs reduce and validated targeted assays are developed with easy hands-on procedures, it is most likely that such assays will become important tools for clinical diagnosis of resistant H. pylori strains.

Anti-Bacterial Agents↗
PubMed2006

First demonstration of the effectiveness of inhibitors of cellular protein kinases in antiviral therapy.

Viral replication and pathogenesis involves many cellular protein kinases, and many specific inhibitors of such kinase have been developed for the treatment of noninfectious diseases. As expected, such drugs have been repeatedly demonstrated to inhibit viral replication in cultured cells. Cellular protein kinases have thus been considered for several years as potentially valid targets for antiviral therapy. However, until recently there was no proof of such activity in vivo. The three papers discussed herein demonstrate that inhibitors of cellular protein kinases are indeed effective for the treatment of virus-induced disease in animal models and human clinical trials.

Animals↗
PubMed2002

Schistosoma mansoni heat shock protein 70 elicits an early humoral immune response in S. mansoni infected baboons.

A study was undertaken to search for DNA recombinant Schistosoma mansoni proteins responsible for eliciting an antibody response from the host at a very early phase after infection. A S. mansoni adult worm cDNA expression library was screened using pooled sera from baboons with four weeks of infection. Based on their specific reactivity with the S. mansoni infected sera and no reactivity when tested against the pre-infection sera from the same baboons, four clones were selected for further studies. Sequence analysis revealed that they were homologous to the S. mansoni heat shock protein 70 (hsp70). The insert sizes of the four selected clones varied from 1150 to 2006 bp. The preliminary characterization for antibody reactivity against a panel of baboon sera showed that the longest clone was the most reactive, eight out of eight acute and three out of four chronic sera reacting positively to this clone. The shortest clone was the least reactive. Our results suggest that the S. mansoni hsp70 elicits an early and strong antibody response in baboons and that antibodies to this protein can be detected in chronically infected animals. Therefore S. mansoni hsp70 may be a valid target for immunodiagnosis. However further studies are needed to identify the portion of the hsp70 that best fits the requirements for a valuable diagnostic antigen.

Animals↗
PubMed1997

Outcomes and their measurement in clinical trials of endosseous oral implants.

The clinical suitability of an oral implant system should be substantiated by well-planned clinical trials that meet the expectations of both the patient and the clinician; i.e., to offer anchorage to a dental prosthesis for one or more decades. The literature often reports on the survival rather than on the success rate, and for the latter a large variety of more or less stringent criteria have been proposed. Although the use of cumulative percentages to assess survival or success on consecutive patients, the so-called Kaplan-Meier statistics, is essential, many publications only report on absolute percentages, thus giving much too optimistic results. Indeed, the large number of recently inserted implants tend to dilute the small fraction that has gone through the maximum observation period. Multi-center studies on consecutive patients who are not selected on the basis of bone quality and volume should be recommended. Otherwise the labeling of the implant should clearly mention which groups; e.g., smokers or patients with limited bone volume are not part of the validated target group. The final outcome measurement would be that an endosseous implant is no longer able to carry out its purpose: to anchor or support successfully a functional dental prosthesis. Like many other clinical evaluations, surrogate parameters have been sought to assess interim success rates. The stability of the marginal bone level is one parameter proposed by many, although bone loss as such is not synonymous with failure. Several implant systems with a roughened surface (plasma sprayed or coated) suffer from progressive marginal bone loss and consequently ongoing loss of implants even after 5 or more years. Those implant systems should be evaluated with cumulative success rates over a period of 10 years. Only those that demonstrated a clustering of both bone and implant loss during the first 1 or 2 years after insertion and subsequently a levelling off for those two parameters-a so-called plateau pattern, should be allowed to draw conclusions after 5 years. Since radiographs reveal only the approximal areas, measurement of the attachment level by means of probing towards a reference point on the abutment should also be performed annually. Intra-oral radiographs can only reveal absence of radiolucency at the bone-implant interface, but do not prove osseointegration. The use of an electronic device offers objective results and reveals even subclinical mobilities of endosseous implants. One can conclude that there is an urgent need for a consensus between health authorities, third parties, and the scientific community to define a set of universally-acceptable success criteria, to impose the use of cumulative success rates, and to ask for observation periods of 10 years for implants that do not demonstrate stable results after one or two years.

Clinical Trials as Topic↗
PubMed2001

Aptamers as reagents for high-throughput screening.

The identification of new drug candidates from chemical libraries is a major component of discovery research in many pharmaceutical companies. Given the large size of many conventional and combinatorial libraries and the rapid increase in the number of possible therapeutic targets, the speed with which efficient high-throughput screening (HTS) assays can be developed can be a rate-limiting step in the discovery process. We show here that aptamers, nucleic acids that bind other molecules with high affinity, can be used as versatile reagents in competition binding HTS assays to identify and optimize small-molecule ligands to protein targets. To illustrate this application, we have used labeled aptamers to platelet-derived growth factor B-chain and wheat germ agglutinin to screen two sets of potential small-molecule ligands. In both cases, binding affinities of all ligands tested (small molecules and aptamers) were strongly correlated with their inhibitory potencies in functional assays. The major advantages of using aptamers in HTS assays are speed of aptamer identification, high affinity of aptamers for protein targets, relatively large aptamer-protein interaction surfaces, and compatibility with various labeling/detection strategies. Aptamers may be particularly useful in HTS assays with protein targets that have no known binding partners such as orphan receptors. Since aptamers that bind to proteins are often specific and potent antagonists of protein function, the use of aptamers for target validation can be coupled with their subsequent use in HTS.

Animals↗
PubMed2005

Oncogenes as novel targets for cancer therapy (part II): Intermediate signaling molecules.

This is the second part of a four-part review on potential therapeutic targeting of oncogenes. The previous part introduced the new technologies responsible for the advancement of oncogene identification, target validation, and drug design. Because of such advances, new specific and more efficient therapeutic agents can be developed for cancer. This part of the review continues the exploration of various oncogenes, which we have grouped within seven categories: growth factors, tyrosine kinases, intermediate signaling molecules, transcription factors, cell cycle regulators, DNA damage repair genes, and genes involved in apoptosis. Part I included a discussion of growth factors and tyrosine kinases. This portion of the review covers intermediate signaling molecules and the various strategies used to inhibit their expression or decrease their activities.

Animals↗
PubMed2005

Oncogenes as novel targets for cancer therapy (part III): transcription factors.

This is the third paper in a four-part serial review on potential therapeutic targeting of oncogenes. The previous parts described the involvement of oncogenes in different aspects of cancer growth and development, and considered the new technologies responsible for the advancement of oncogene identification, target validation, and drug design. Because of such advances, new specific and more efficient therapeutic agents can be developed for cancer. This part of the review continues the exploration of various oncogenes that we have grouped within seven categories: growth factors, tyrosine kinases, intermediate signaling molecules, transcription factors, cell cycle regulators, DNA damage repair genes, and genes involved in apoptosis. Part one discussed growth factors and tyrosine kinases and part two discussed intermediate signaling molecules. This portion of the review covers transcription factors and the various strategies being used to inhibit their expression or decrease their activities.

Animals↗
PubMed2003

Ligand-protein docking: cancer research at the interface between biology and chemistry.

In recent years there has been a growing interest in computer-based screening. One of the driving forces has been the increased efficiency of protein crystallography leading to the real possibility of using structure-based design as a significant contributor to the discovery of novel ligands. In 1957 after 22 years of work the first protein structure, determined by x-ray crystallography was produced. Now the process has become increasingly automated and nearly 20,000 protein structures are available in the Protein Data Bank (PDB). Equally, progress in genomics will result in a great expansion of validated targets for cancer therapy. The understanding of the relationships between structure and function of gene products will be one of the key routes to new therapeutic advances. The challenge now is to use this data in the discovery of novel therapeutics. One approach is obviously to synthesize molecules and co-crystallize or soak them into the protein crystal and so determine the position and interaction of the molecule with the protein. The structural information obtained (where does the molecule bind; what are the ligand/protein/solvent interactions?) can be invaluable in the generation of novel molecules or in the re-design of existing molecules whose drug properties are not optimal. However, when dealing with large numbers (millions) of molecules, when crystallization is difficult or in testing hypotheses, a significant contribution can be made using computer based screening methods. In order to use the structural information derived from x-ray crystallography (or other sources, for example NMR or homology modelling) when evaluating the utility of a novel ligand, we need to understand where in the protein (or other macromolecule such as RNA) the ligand is likely to bind and also if possible, the strength of the binding interactions. This problem is known as the 'docking problem'. There have been many approaches to the solution of this problem over the last ten years. For example, some methods rely on complex molecular dynamics simulations while others use less costly graph matching approaches. There is generally a compromise between speed and accuracy, with some methods giving much more information and insight into the nature of the protein/ligand interactions and other methods optimised for speed of docking thousands of putative ligands. We will describe some of the more common methods and algorithms used to solve the docking problem and in particular, we will review recent applications in cancer research.

Animals↗
PubMed2005

Novel chemical strategies for thymidylate synthase inhibition.

Thymidylate synthase (TS) is a well-validated target for cancer chemotherapy. TS was established as the principal target of the widely used anticancer drug 5-fluorouracil (5FU). The 5FU metabolite FdUMP forms a covalent complex with TS that is stabilized by 5-formyl tetrahydrofolate (leucovorin; LV). Numerous chemical strategies have been employed to develop novel TS inhibitors that are superior to 5FU/LV. 5FU is non-ideal as a TS-inhibitory drug because it is only inefficiently converted to FdUMP, while the remainder of the administered dose is converted to toxic metabolites. My laboratory has explored the utility of FdUMP[N] compounds (oligodeoxynucleotides comprised of FdUMP nucleotides) as FdUMP pro-drugs. FdUMP[N] compounds result in potent TS-inhibition, and display many advantages relative to 5FU/LV. A number of other chemical strategies have also been employed to develop pro-drugs, or metabolic precursors of FdUMP, and several of these strategies will be reviewed. In addition to chemical strategies to develop FdUMP pro-drugs, a number of chemical strategies have been devised to develop molecules that resemble the reduced folate co-factor required for TS catalysis. The synthesis of antifolates that have TS-inhibitory activity, such as Raltitrexed, has resulted in compounds that are effective and specific TS-inhibitors and, in some cases, have clinical potential. Chemical strategies that target TS mRNA for destruction are also being explored as potential chemotherapeutics. These diverse chemical approaches to control TS activity in tumor cells for the treatment of cancer will be reviewed.

Animals↗
PubMed2005

Antisense oligonucleotides: the state of the art.

The use of antisense oligonucleotides as therapeutic agents has generated considerable enthusiasm in the research and medical community. Antisense oligonucleotides as therapeutic agents were proposed as far back as in the 1970s when the antisense strategy was initially developed. Nonetheless, it has taken almost a quarter of a century for this potential to be realized. The principle of antisense technology is the sequence-specific binding of an antisense oligonucleotide to target mRNA, resulting in the prevention of gene translation. The specificity of hybridization by Watson-Crick base pairing make antisense oligonucleotides attractive as tools for targeted validation and functionalization, and as therapeutics to selectively modulate the expression of genes involved in the pathogenesis of diseases. The last few years have seen a rapid increase in the number of antisense molecules progressing past Phase I, II and III clinical trials. This review outlines the basic concept of the antisense technology, its development and recent potential therapeutic applications.

Antineoplastic Agents↗
PubMed2001

PET studies with carbon-11 radioligands in neuropsychopharmacological drug development.

A basic problem in the discovery and development of novel drugs to be used in the treatment of neurological and psychiatric disorders is the absence of relevant in vitro or in vivo animal models that can yield results which can be extrapolated to man. Drug research now benefits from the fast development of functional imaging techniques such as positron emission tomography (PET) which trace radiolabelled molecules directly in the human brain. PET uses molecules that are labelled with short-lived radionuclides and injected intravenously into experimental animals, human volunteers or patients. The most frequent approach is to study how an unlabelled drug inhibits specific binding of a well characterised selective PET radioligand. The alternative direct approach is to radiolabel a new potential drug and to trace its uptake, anatomical distribution and binding in brain. Furthermore, the effects of a novel drug on physiological-biochemical parameters, such as glucose metabolism or blood flow, can also be assessed. The demonstration of quantitative relationships between drug binding in vivo and drug effects in patients is used to validate targets for drug action, to correlate pharmacological and physiological effects, and to optimise clinical treatment.

Animals↗
PubMed2004

Monitoring therapy with gene expression profiling reveals physiological differences in drug action.

Gene expression profiling has become a versatile tool for biomedical research, which allows the assessment of a wide variety of basic questions in cellular regulation, in particular when a large number of molecular parameters have changed. There are various applications in drug research for which gene expression profiling is a very suitable approach. This includes: target identification, target validation, validation of drug specificity and monitoring of drug action during therapy. The focus of this article is the therapy monitoring and the interpretation of the gene expression profiles in respect to physiological differences of drug action. As an example, we will discuss changes in gene expression in blood samples from CML patients treated with the tyrosine kinase inhibitor (imatinib mesylate) and compare the observed effects on gene expression with the effects of IFNalpha treatment. In comparison with other examples of therapy monitoring the potential of this application of gene expression profiling for optimizing individual therapy will be discussed.

Animals↗
PubMed2006

CFTR chloride channel drug discovery--inhibitors as antidiarrheals and activators for therapy of cystic fibrosis.

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a cAMP-activated chloride channel expressed in epithelia in the lung, intestine, pancreas, testis and other tissues, where it facilitates transepithelial fluid transport. In the intestine CFTR provides the major route for chloride secretion in certain diarrheas. Mutations in CFTR cause the hereditary disease cystic fibrosis, where chronic lung infection and deterioration in lung function cause early death. CFTR is a well-validated targeted for development of inhibitors for therapy of secretory diarrheas and activators for therapy in cystic fibrosis. Our lab has identified and optimized small molecule inhibitors of CFTR, as well as activators of DeltaF508-CFTR, the most common mutant CFTR causing cystic fibrosis. High-throughput screening of small molecule collections utilizing a cell-based fluorescence assay of halide transport yielded thiazolidinone and glycine hydrazide CFTR inhibitors that block enterotoxin-mediated secretory diarrhea in rodent models, including a class of non-absorbable inhibitors that target the CFTR pore at its external entrance. Benzothiophene, phenylglycine and sulfonamide potentiators were identified that correct the defective gating of DeltaF508-CFTR chloride channels, and other small molecules that correct its defective cellular processing. Small molecule modulators of CFTR function may be useful in the treatment of cystic fibrosis, secretory diarrhea and polycystic kidney disease.

Animals↗
PubMed2003

Cytokine antibody arrays: a promising tool to identify molecular targets for drug discovery.

Cytokines play important roles in normal cell functions and changes in cytokines have been implicated in many diseases. Recent efforts have focused on developing cytokine antibody arrays. These arrays allow investigators to simultaneously detect multiple cytokines in qualitative and quantitative ways. Cytokine antibody array systems feature high sensitivity, specificity and throughput. This novel technology opens up an expanding spectrum of applications in drug discovery, including target discovery, target validation, screening for lead compounds, compound optimization and clinical trials.

Antibodies↗
PubMed2005

The future of post-genomic biology at the proteomic level: an outlook.

Drug discovery and early-stage drugs and biomarkers development is a continuous adaptation and maturation process. The cycle of changes based on new findings is coupled with shifts in research priorities and make this part of pharmaceutical research a challenging endeavour. Over the last years, the emphasis on genomics has shifted to proteomics, the science of understanding how proteins translate gene information into function, and metabonomics, the science of small metabolites that are further apart from genomic projects. Proteomics describes the analysis of the protein complement of a biological sample with respect to temporal and spatial resolution. This technology is based on separation of complex protein mixtures by 2D gel-electrophoresis, in gel digest and mass spectrometric analysis of the protein fragments. Proteomics has been recently flanked by peptidomics, a new research direction aimed at the comprehensive analysis of small (1-20 kDa) polypeptides, thus covering the gap between proteomics and metabonomics. The refinement of peptidomics is based on an essential paradigm related to modularity and diversity. Peptides are a paramount example of how one single gene can release multiple functionalities. We can expect fast progress in understanding protein and peptide networks from a systems biology approach ending in the discovery of new peptide targets. However, the way from a complex sample to potential diagnostic and therapeutic targets will depend on technological developments and from the ability to discriminate true disease-related signals from false positive and negative signals, and the way from target discovery to target validation will not be short.

Aged↗
PubMed2005

Ribozymes, DNAzymes and small interfering RNAs as therapeutics.

Selective gene silencing by nucleic acid enzymes has provided researchers with a new strategy to block gene expression and drug target validation. Ribozymes, DNAzymes and small interfering RNAs (siRNAs) are being explored as genetic inhibitors of gene expression as well as potential therapeutics against viral infections, inflammatory disorders, haematological diseases and cancers. We review the mode of action of these molecules, with special emphasis on their construction and the possibility to enhance their serum half-lives via specific chemical modifications. Their potential use in cell cultures and in animal models for disease is also highlighted.

Animals↗
PubMed2005

Recent advances in discovery and development of promising therapeutics against hepatitis C virus NS5B RNA-dependent RNA polymerase.

Lack of highly effective and safe therapeutics for hepatitis C virus (HCV) infection provides an opportunity as well as a challenge to discover novel and potent anti-HCV drugs. HCV NS5B RNA-dependent RNA polymerase (RdRp) is responsible for viral genome replication and thus constitutes a valid target for therapeutic intervention. To date, numerous HCV NS5B RdRp inhibitors have been discovered. This review focuses on the recent advances in discovery, mechanism of action studies and biological characterization of several distinct classes of potent inhibitors for NS5B RdRp. The clinical efficacy and developmental status of several promising compounds are also outlined.

Animals↗