Blocking ?-sheet formation offers hope for diseases from diabetes to Alzheimer's.
Blocking ?-sheet formation offers hope for diseases from diabetes to Alzheimer’s.
A peptide that inhibits one of the pathological processes underlying type 2 diabetes has been developed by Israeli scientists. Their approach could be useful in designing inhibitors to slow a variety of other diseases, they suggest.
The inappropriate clumping of amyloid proteins is linked with a number of disorders, including Alzheimer’s, prion diseases and type 2 diabetes. Clumped proteins lose their native conformation and adopt ordered, stacked ?-sheet structures. Preventing the proteins from forming ?-sheets - using molecules dubbed ?-breakers - could slow the deposition of fibrils, suggests Ehud Gazit of Tel Aviv University, Israel.
Current ?-breakers take advantage of the natural ?-breaking properties of the amino acid proline. Now, Gazit has exploited the stronger ?-breaking properties of another molecule -?-aminoisobutyric acid, or Aib.
Gazit’s team tested the ability of Aib peptides to inhibit amyloid formation by using the human islet amyloid polypeptide (hIAPP) as a test case. This protein is stored in the islets of Langerhans cells in the pancreas. IAPP fibril clumps are thought to destroy these insulin-producing cells, causing diabetes.
Having identified the sequence in hIAPP that recognises other IAPP molecules, the team produced peptides corresponding to the recognition sequence, but with two Aib molecules instead of the natural amino acids. They wanted to keep the recognition properties of the fragment, but abolish its ability to assemble into amyloid fibrils.
A tenfold excess of the ?-breaker dramatically reduced the aggregation of the hIAPP peptide. ’These results clearly indicate that Aib-containing peptides have great potential as inhibitors of hIAPP amyloid fibril formation,’ said Gazit. He suggests the approach could generate many molecules with highly specific chemical properties for use in other amyloid diseases.
’The use of ?-sheet breakers is currently the direction of choice for design of inhibitors of amyloid formation for all types of amyloid disease,’ agreed UK researcher Anne Clark of the Oxford Centre for Diabetes, Endocrinology and Metabolism. ’Gazit’s research is showing a useful way to prevent fibril formation from IAPP in vitro’.
But she is unsure whether this Aib inhibitor has clinical potential. ’[?-breakers are] showing most success in patients with severe systemic amyloidoses where the amyloid load is extensive and can be monitored by whole body imaging,’ she said. In diabetes, the amyloid deposits are too small to be seen with in vivo imaging, so any therapy that targets islet amyloid production would need to show improvement of islet function over many years.
’These types of therapy are low on the list of useful drug targets for the increasing population of subjects with diabetes,’ said Clark.
S Gilead and E Gazit, Angewandte Chemie Int. Ed., 2004, 43, 4041