The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites.

Protein degradation is regulated during the cell cycle of all eukaryotic cells and is mediated by the ubiquitin-proteasome pathway. Potent and specific peptide-derived inhibitors of the 20S proteasome have been developed recently as anti-cancer agents, based on their ability to induce apoptosis in rapidly dividing cells. Here, we tested a novel small molecule dipeptidyl boronic acid proteasome inhibitor, named MLN-273 on blood and liver stages of Plasmodium species, both of which undergo active replication, probably requiring extensive proteasome activity. The inhibitor blocked Plasmodium falciparum erythrocytic development at an early ring stage as well as P. berghei exoerythrocytic progression to schizonts. Importantly, neither uninfected erythrocytes nor hepatocytes were affected by the drug. MLN-273 caused an overall reduction in protein degradation in P. falciparum, as demonstrated by immunoblots using anti-ubiquitin antibodies to label ubiquitin-tagged protein conjugates. This led us to conclude that the target of the drug was the parasite proteasome. The fact that proteasome inhibitors are presently used as anti-cancer drugs in humans forms a solid basis for further development and makes them potentially attractive drugs also for malaria chemotherapy.

Lessons in Software Evolution Learned by Listening to Smalltalk

The biggest challenge facing software developers today is how to gracefully evolve complex software systems in the face of changing requirements. We clearly need software systems to be more dynamic, compositional and model-centric, but instead we continue to build systems that are static, baroque and inflexible. How can we better build change-enabled systems in the future? To answer this question, we propose to look back to one of the most successful systems to support change, namely Smalltalk. We briefly introduce Smalltalk with a few simple examples, and draw some lessons for software evolution. Smalltalk's simplicity, its reflective design, and its highly dynamic nature all go a long way towards enabling change in Smalltalk applications. We then illustrate how these lessons work in practice by reviewing a number of research projects that support software evolution by exploiting Smalltalk's design. We conclude by summarizing open issues and challenges for change-enabled systems of the future.