Drug discovery and vaccine development using mixture-based synthetic combinatorial libraries.

The approaches and concepts that encompass combinatorial chemistry represent a paradigm shift in drug discovery and basic research. Viewed initially as a curiosity by the pharmaceutical industry, combinatorial chemistry approaches are now recognized as essential drug discovery tools that decrease the time taken for discovery and increase the throughput of chemical screening by as much as 1000-fold. Although the use of mixture-based synthetic combinatorial libraries was one of the first approaches presented, its inherent strengths are only recently being recognized. Numerous mixture-based libraries of peptides, peptidomimetics and heterocycles have been synthesized and deconvoluted using the positional scanning approach. Mixture-based library approaches for drug discovery and vaccine development will be reviewed herein.

Learning foraging thresholds for lizards: an analysis of a simple learning algorithm

This paper gives proof of convergence for a learning algorithm that describes how anoles (lizards found in the Caribbean) learn foraging threshold distance. An anole will pursue a prey if and only if it is within this threshold of the anole's perch. The learning algorithm was proposed by Roughgarden and his colleagues. They experimentally determined that this algorithm quickly converges to the foraging threshold that is predicted by optimal foraging theory. We provide analytic confirmation that the optimal foraging behavior as predicted by Roughgarden's model can be attained by a lizard that follows this simple and zoologically plausible rule of thumb. Copyright 1999 Academic Press.

Factorial optimization of a six-cellulase mixture

A factorial experimental design approach was used to optimize mixtures of six cellulases (five Thermomonospora fusca cellulases and plus/minus Trichoderma reesei CBHI along with beta-glucosidase) so as to maximize the glucose produced from filter paper. Optimized mixture A and mixture B produced glucose at 25 and 8.3 µmol glucose/µmol enzyme/min, respectively, which are 8 and 1.5 times higher than the sum of the activity of the individual cellulases. In both mixtures, the glucose yield depended on the ratio and the cellulases used. Most enzymes showed synergistic interactions that increased the glucose yield. The yield of glucose with the optimum mixtures depended on the total enzyme concentration. Copyright 1998 John Wiley & Sons, Inc.

Fed-batch production of thermomonospora fusca endoglucanase by recombinant streptomyces lividans

The factors affecting the production of a Thermomonospora fusca endoglucanase by a recombinant Streptomyces lividans strain were studied in a fermentor with glucose addition controlled by a pH-stat. The recombinant plasmid was stable for 35 generations with constant endoglucanase productivity. Glucose and peptone were used as the carbon and nitrogen sources. Addition of Tween-80 increased endoglucanase production twofold. A significant decrease in endoglucanase production was observed at low aeration. During fed-batch cultivation, pulse feeding (6 g/L) of a glucose-ammonium sulfate solution was optimal for endoglucanase production. With higher concentrations of glucose (15 g/L), a significant amount of organic acid, including acetic acid, was produced, which inhibited cell growth and endoglucanase production. Under optimum conditions, 1.7 U/mL of endoglucanase were produced. Copyright 1998 John Wiley & Sons, Inc.