Amyloid inhibitors are aggregates too


A new understanding of the way protein inhibitors work may have major implications in the development of drugs for Alzheimer’s and other neurodegenerative diseases. Scientists have discovered a significant feature in the way that known amyloid inhibitors work, according to a paper to be published online this week in Nature Chemical Biology.

Several neurodegenerative diseases may be caused by the collection of various proteins into large clumps of disordered proteins, known as fibrils. A common strategy to try to find cures for these diseases is to search for molecules that can prevent formation of these fibrils or even cause them to break apart.

Brian Shoichet and colleagues demonstrate that the molecules that have been identified so far in this search act in an unusual manner: the compounds themselves form large groups, known as aggregates, which then act on the proteins to prevent the undesired clumping. The authors also found that other compounds not previously identified as amyloid inhibitors but known to form aggregates also stop the proteins from clumping up. This result will require a significant re-evaluation of the way in which drug developers approach Alzheimer’s disease.

Author contact:
Brian Shoichet (University of California San Francisco, San Francisco, CA. USA)
Tel: +1 415 514 4126; E-mail: shoichet@cgl.ucsf.edu

Adding a pinch of sugar


Enzymes can be engineered to decorate small molecules with a wide variety of sugars. The biological activity of many natural products—small molecules that 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.


Author contact:

Jon Thorson (University of Wisconsin, Madison, WI, USA)

Tel: +1 608 262 3829; E-mail: jsthorson@pharmacy.wisc.edu



Watching protein-cutting enzymes in action

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.


Author contact:

Matthew Bogyo (Stanford University, Stanford, CA, USA)

Tel: +1 650 725 4132; E-mail: mbogyo@stanford.edu