A range of debilitating human diseases including Alzheimer’s, Parkinson’s and Huntington’s disease and type 2 diabetes (T2D) are associated with misfolding of certain proteins and their subsequent aggregation into toxic fibers, called amyloids. These diseases differ in the type of the protein involved, location of aggregation and clinical manifestations but share a common mechanism of stacking and fibrillization. Human Islet Polypeptide (hIAPP) is a protein that is synthesized, stored and secreted together with insulin and helps in gastric emptying in healthy individuals. However, in response to metabolic stress and spiking blood sugar levels, hIAPP misfolds into β-sheets, self-assembles into amyloids and shuts down the insulin production, leading to T2D.
The research group led by Dr. Rahman Shah Zaib Saleem at the Department of Chemistry and Chemical Engineering is currently working on synthesis and identification of new small organic molecules that can target, bind and prevent hIAPP aggregation, keeping it in its native state. Recent outcome from this project is published in Bioorganic Chemistry, a prestigious journal in the field of medicinal chemistry research. The research titled, ‘Synthesis and identification of novel pryidazinylpyrazolone based diazo compounds as inhibitors of human islet amyloid polypeptide aggregation’ presents a lead molecule (research code name SSE15314) that completely inhibits hIAPP fibrillization. The work was carried out at LUMS by student, Syed Usama Bin Farrukh (during his MS research work) and Ibrahim Javed at Monash Institute of Pharmaceutical Sciences, Monash University.
“Drugs that are currently available in the market either sensitize the production of insulin, exhausting the remaining insulin producing pancreatic cells, or lower down the glucose production in liver. Drug molecules that inhibit the toxic aggregation of hIAPP in the pancreas, can provide effective opportunities to treat the basic etiology of diabetes at early stages,” shared Syed Usama Bin Farrukh.
‘’While aggregating, amyloid proteins can cross-talk with each other and induce the onset of Alzheimer’s or Parkinson’s disease in a diabetic patient or vice versa. Targeting the basic aggregation phenomenon in amyloidogenesis with a single drug molecule, together with efficient delivery systems, can target multiple protein-misfolding diseases in one shot,’’ said Ibrahim Javed.
“Drug discovery is a long process and the identification of a lead compound is just a start,” said Dr. Saleem. He is confident that the optimization of such small molecules could lead further down the road to new potential drug candidates against diabetes and other amyloid diseases.
The article can be accessed here.
