Will genetics really revolutionize the drug discovery process?

Genetics has played only a modest role in drug discovery, but new technologies will radically change this. Whole genome sequencing will identify new drug discovery targets, and emerging methods for the determination of gene function will increase the ability to select robust targets. Detection of single nucleotide polymorphisms and common polymorphisms will enhance the investigation of polygenic diseases and the use of genetics in drug development. Oligonucleotide arraying technologies will allow analysis of gene expression patterns in novel ways.     

The chemical-biological interface: developments in automated and miniaturised screening technology

The rapidly changing developments in genomics and combinatorial chemistry, generating new drug targets and large numbers of compounds, have caused a revolution in high-throughput screening technologies. Key to this revolution has been the introduction of robotics and automation, together with new biological assay technologies (e.g., homogeneous time resolved fluorescence). With ever increasing workloads, together with economic and logistical constraints, miniaturisation is rapidly becoming essential for the future of high-throughput screening and combinatorial chemistry. This is evident from the introduction of high-density microtitre plates, small volume liquid handling robots and associated detection technology.     

Exploiting the complete yeast genome sequence

The completion of the genome sequence of the budding yeast Saccharomyces cerevisiae marks the dawn of an exciting new era in eukaryotic biology that will bring with it a new understanding of yeast, other model organisms, and human beings. This body of sequence data benefits yeast researchers by obviating the need for piecemeal sequencing of genes, and allows researchers working with other organisms to tap into experimental advantages inherent in the yeast system and learn from functionally characterized yeast gene products which are their proteins of interest. In addition, the yeast post-genome sequence era is serving as a testing ground for powerful new technologies, and proven experimental approaches are being applied for the first time in a comprehensive fashion on a complete eukaryotic gene repertoire.     

Xenogeneic organ transplantation

Over the past few years, several major advances have occurred in the understanding of how the humoral and cellular immune system of humans recognizes and destroys transplant cells, tissues and organs derived from animal sources. Consequently, armed with this new knowledge, several laboratories have now developed novel immunoprotective technologies that may allow xenotransplantation to be clinically feasible.     

Oligosaccharide receptors for bacteria: a view to a kill

Oligosaccharide recognition is a major means of bacterial—host cell attachment. Bacterial—host receptor binding can subvert host signaling pathways to cause pathology. In addition, pathogenic bacteria can utilize more than one recognition system to bind host cells. Recent studies of Helicobacter pylori illustrate both these points. Together with this redundancy in recognition, the importance of multivalent sugar binding has become apparent. Multivalent sugar receptor analogs have been used to both prevent and detach adherent bacteria. Several new chemical technologies for the generation of bioactive glycopolymers have been developed and may be successfully adapted to address both these issues.     

Inkjet dispensing technology: applications in drug discovery

The past year has seen significant advances in the reduction to practice of inkjet dispensing technology in drug discovery applications. Although much of the work in this area has been done by relatively few ‘early innovators’, broader acceptance of the feasibility of the use of inkjet dispensing is on the rise. Of the three main areas of drug discovery — genomics, high-throughput screening, and combinatorial chemistry — high-throughput screening has had the most applications to date. The burgeoning field of genomics has seen rapid incorporation of technologies that enable miniaturization of gene expression experiments. Inkjet dispensing has a clear role in this effort. Finally, as the miniaturization needs of combinatorial chemistry become more clear, inkjet dispensing technology will potentially play a role.     

Solid-phase oligosaccharide synthesis and related technologies

Research efforts directed at the development of methodologies effective for solid-phase synthesis of oligosaccharides have resulted in a number of impressive achievements. In addition, closely related technologies, such as soluble polymer-supported synthesis and fluorous synthesis of the same class of molecules, have proved to be quite promising.     

Bacterial genome sequencing and drug discovery

The availability of bacterial genome sequence information has opened up many new strategies for antibacterial drug hunting. There are obvious benefits for the idetification and evaluation of new drug targets, but genomic-based technology is also beginning to provide new tools for the downstream, preclinical, optimisation of compounds. The greatest benefit from these new approaches lies in the ability to examine the entire genome (or several genomes) simultaneously and in total. In this way, one potential target can be evaluated against another, and either the total effects of functional impairment can be established or the effects of a compound can be compared across species.     

The integration of microarray information in the drug development process

In the past year, microarray technologies have moved beyond the proof-of-principle stage. Microarrays are now being used for genome-wide expression monitoring, large-scale polymorphism screening and mapping, and for the evaluation of drug candidates.     

The evolution of the Hox cluster: insights from outgroups

Two burgeoning research trends are helping to reconstruct the evolution of the Hox cluster with greater detail and clarity. First, Hox genes are being studied in a broader phylogenetic sampling of taxa: the past year has witnessed important new data from teleost fishes, onychophorans, myriapods, polychaetes, glossiphoniid leeches, ribbon worms, and sea anemones. Second, commonly accepted notions of animal relationships are being challenged by alternative phylogenetic hypotheses that are causing us to rethink the evolutionary relationships of important metazoan lineages, especially arthropods, annelids, nematodes, and platyhelminthes.     

S-phase and DNA-damage checkpoints: a tale of two yeasts

Many genes required for the S-phase and DNA-damage checkpoints have been identified in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe. This year many checkpoint genes have been sequenced, providing new information about the mechanism of checkpoint control. Several of these genes are conserved between the two yeasts but others are species-specific.     

Will combinatorial chemistry deliver real medicines?

Over the next decade, the impact of library synthesis will play a major role in shortening the lead optimization phase of drug discovery. The prognosis for combinatorial chemistry to discover fundamentally different new classes of therapeutically active small molecules against some of the more difficult biological targets is less certain. Expectations are high because the technology potentially allows us to sample available drug space by synthesizing all possible small molecule ligands (variously estimated to be between 10³⁰–10⁵⁰ compounds). Some caution is advised, however, since, despite recent increases in high-throughput screening of substantially greater numbers of synthetic compounds and natural products, we are not routinely finding a plethora of new structures. The outcome may be that combinatorial chemistry offers us the ability to work faster on finding ligands for well-established tractable targets, such as G-protein-coupled receptors, ion channels or proteases, rather than, say, the more complex protein—protein interactions which from the majority of targets in signal transduction pathways.     

Applications of dendrimers in bio-organic chemistry

Dendrimers represent a new class of highly branched polymers whose interior cavities and multiple peripheral groups facilitate potential applications in biomedicine and bio-organic chemistry. Major advances in the past year were made in the synthesis and study of new carbohydrate, nucleic acid, and peptide dendrimers, as well as in the use of dendrimers as magnetic resonance imaging contrast agents, as agents for cellular delivery of nucleic acids, and as scaffolds for biomimetic systems.     

Antifreeze proteins

Antifreeze proteins comprise a structurally diverse class of proteins that inhibit the growth of ice. Recently, new AFP types have been discovered; more active AFPs have been isolated; antecedents have been recognized supporting the notion of recent, multiple origins; and detailed structures have emerged leading to models for their adsorption to ice     

Metazoan phylogenies: falling into place or falling to pieces? A palaeontological perspective

Metazoan phylogeny is in a state of ferment, stirred by the addition of new molecular trees as well as controversial interpretations of molecular ‘clocks’. Concerning the latter topic, the clocks recurrently point to divergence times substantially older than the known fossil record. Some attempt reconciliation by appealing to a conveniently cryptic interval prior to the first fossils. This effectively reduces the fossil record to an erratic search-light giving only glimpses into the true evolutionary history. Other options, however, remain open. Molecular clocks may themselves run erratically and what happens in molecular history may not coincide with the emergence of body plans.     

Chemistry and physics of giant vesicles as biomembrane models

The giant vesicle is becoming an object of intense scrutiny by chemists, biologists, and physicists who are interested in membrane behavior. Recent advances include new models to explain morphological changes, new experimental methods for studying vesicle adhesion, layering and adsorption, and new cataloging of ‘cytomimetic’ processes.     

Dorsal-ventral signaling in limb development

In both Drosophila wings and vertebrate limbs, signaling between dorsal and ventral cells establishes an organizer that promotes limb formation. Significant progress has been made recently towards characterizing the signaling interactions that occur at the dorsal—ventral limb border. Studies of chicks have indicated that, as in Drosophila, this signaling process requires the participation of Fringe. Studies of Drosophila have indicated that Fringe functions by inhibiting the ability of Notch to be activated by one ligand, Serrate, while potentiating the ability of Notch to be activated by another ligand, Delta. Recent studies of both Drosophila and vertebrates have also shed new light on the signaling activity of the dorsal—ventral boundary limb organizer, and have highlighted how this organizer is maintained by feedback mechanisms with neighboring cells.     

Carbamoyl phosphate synthetase: a tunnel runs through it

The direct transfer of metabolites from one protein to another in a biochemical pathway or between one active site and another within a single enzyme has been described as substrate channeling. The first structural visualization of such a phenomenon was provided by the X-ray crystallographic analysis of tryptophan synthase, in which a tunnel of approximately 25 Å in length was observed. The recently determined three-dimensional structure of carbamoyl phosphate synthetase sets a new long distance record in that the three active sites are separated by nearly 100 Å.     

Everything in moderation: Archaea as ‘non-extremophiles’

Well characterized and cultivated archaea are prokaryotic specialists that thrive in habitats of elevated temperature, low pH, high salinity, or strict anoxia. Recently, however, new groups of abundant, uncultivated archaea have been found to be widespread in more pedestrian biotopes, including marine plankton, terrestrial soils, lakes, marine and freshwater sediments, and in association with metazoa. Research efforts are presently focused on characterizing the physiology, biochemistry and genetics of these abundant and cosmopolitan but poorly understood archaea.