A three-in-one approach to cancer vaccines

A single chemical structure that incorporates three vaccine components could prove powerful in treating cancer, according to a paper in the October issue of Nature Chemical Biology. Sugars are often highly expressed on the outside of cancer cells, and eliciting an immune response to these sugars could be an important vaccine strategy.

Previous attempts to develop anticancer vaccines against these overexpressed sugars have involved 'two-component' vaccines, which combine molecules that can induce antibody production by two different routes into a single chemical entity. However, these vaccines require very high levels of adjuvants— additional chemicals that are used to boost the immune response being elicited by the vaccine.

Geert-Jan Boons and colleagues have now developed a 'three-component' vaccine that chemically links the adjuvant to two other vaccine components. Chemically connecting these three vaccine pieces proved to be exceptionally powerful in inducing an immune response in mice. This vaccine strategy can now be tested for its ability to combat cancer, and the three-component approach could be applied to other vaccine targets.

Adding a pinch of sugar

Enzymes can be engineered to decorate small molecules with a wide variety of sugars, according to a paper in the October issue of Nature Chemical Biology. The biological activity of many natural products — small molecules that are occur naturally and form the basis for many drugs — is influenced by the addition of a sugar molecule. Thus, varying these sugar molecules can be important when looking for new drug leads; however, altering these sugars can be challenging using glycosyltransferases (enzymes that transfer sugars) because they typically only function with a narrow range of sugars and small molecules.

Jon Thorson and colleagues used a process called directed evolution, in which random mutations are introduced at select positions in an enzyme and a large number of mutated enzymes are screened for the desired activity. They were able to engineer a glycosyltransferase that can transfer a wide range of sugar molecules onto a variety of therapeutically important small molecules. These 'mutant' enzymes can now be used in the search for new therapeutics.

Watching protein-cutting enzymes in action in tumours

The activity of proteases — enzymes that cut other proteins and are important in diseases such as AIDS and cancer — can be imaged in living animals with 'smart probes' using a method reported in the October issue of Nature Chemical Biology. Cathepsin proteases are specific protein-cleaving enzymes involved in tumour formation and metastasis, and are important targets for diagnosing and treating cancer.

Using probes that only fluoresce when they react with active proteases, Matthew Bogyo and colleagues have imaged cathepsin activity in the tumours of living mice. Because the probes form a covalent bond (a permanent connection) with cathepsin, in vitro experiments can directly follow in vivo imaging to provide a mechanistic explanation for what is observed. The authors demonstrate that these probes are useful for testing the effectiveness of potential drugs.

Robust immune responses elicited by a fully synthetic three-component vaccine

Sampat Ingale, Margreet A Wolfert, Jidnyasa Gaekwad, Therese Buskas and Geert-Jan Boons

Published online: 02 September 2007 | doi 10.1038/nchembio.2007.25

Abstract | Full text | PDF | Supplementary information

Expanding the promiscuity of a natural-product glycosyltransferase by directed evolution

Gavin J Williams, Changsheng Zhang and Jon S Thorson

Published online: 09 September 2007 | doi 10.1038/nchembio.2007.28

Abstract | Full text | PDF | Supplementary information

Noninvasive optical imaging of cysteine protease activity using fluorescently quenched activity-based probes

Galia Blum, Georges von Degenfeld, Milton J Merchant, Helen M Blau and Matthew Bogyo

Published online: 09 September 2007 | doi 10.1038/nchembio.2007.26

Abstract | Full text | PDF | Supplementary information