Volume 5 Issue 2, February 2009

Autofluorescent proteins have become indispensable in our quest to visualize molecular events in living cells. Further progress in the visualization and quantification of all biochemical activities of the cell will require the introduction of additional and complementary methods for sensing and probing biomolecules. Here I highlight some of the areas where the development of new probes and labeling methods is eagerly awaited and where chemical biologists could make important contributions.

Chemical biology is well defined at its core—chemistry helping to answer biological questions—yet the boundaries are rather fuzzy. What are the differences between chemical biology and pharmacology? Is intracellular imaging a branch of chemical biology, and what about screening libraries? At Chemical Biology 2008, held in Heidelberg in October, participants heard presentations covering all these topics and more.

Monomeric fluorescent proteins that change their emission characteristics as they mature have been successfully used to study the spatial and temporal dynamics of lysosome-associated membrane protein type 2A. This methodology provides a new means of studying cellular events in a dynamic mode.

Rotaviruses have been designated as 'sialidase sensitive' or 'sialidase insensitive', based on how their entry into cells is affected by treating cells with sialidases. A new study uses multiple methods, including saturation transfer difference NMR spectroscopy, to elucidate interesting interactions involving terminal and internal sialic acid moieties, concluding that 'sialidase insensitive' does not mean 'sialic acid independent'.

The 'RNA World' hypothesis presupposes the existence of a catalytic RNA that can polymerize nucleotide triphosphates to replicate a template, but such chemistry has not previously been detected in natural ribozymes. Detailed investigation of the products of a bacterial self-splicing group I intron now suggest that such ribozymes indeed exist in nature.

Wnt signals are seemingly ubiquitous in biology, controlling processes as diverse as bristle patterning in flies and tissue regeneration in humans. A new report describes the discovery of small molecules that inhibit Wnt signaling by two unprecedented mechanisms, paving the way for fundamental studies and perhaps improved treatment of colon cancer.

Syntheses of natural product–like compound libraries with high scaffold diversity have proven hard to develop. A strategy employing metathesis cascades to 'zip up' a set of unsaturated building blocks differently connected by variable linkers demonstrates that over 80 distinct scaffold classes can be synthesized in one go.

Access to new analogs of the tetracycline family of antibiotics has thus far been limited to compounds that can be prepared by modification of the isolable natural products. An efficient total-synthesis pathway with extraordinary flexibility has now made it possible to identify new tetracycline derivatives with activity against a wide range of antibiotic-resistant bacteria.