Executive Summary : | Elevated LDL cholesterol is a significant risk factor for cardiovascular diseases, affecting approximately 20 million lives annually. Statins are the primary treatment option for most patients, but prolonged use can lead to side effects like muscle pain, sleep disorder, and type 2 diabetes. This necessitates the development of new drugs against hypercholesterolemia with novel modes of action. Current drug discovery efforts focus on PCSK9, which plays a key role in lipid mechanisms. Two monoclonal antibodies have been approved for clinical use, but their high cost and administration problems necessitate the development of small-molecule-based therapeutic agents. Intense research from pharmaceutical industries and academic institutions has yielded promising leads, but only one candidate from Merck has advanced to phase 2b clinical trial. This proposal aims to identify new candidates using innovative approaches. The LDLR recognition domain of PCSK9 is flat and lacks deep binding pockets, making peptide-based therapeutics highly relevant. New designs capable of accessing a larger number of 'hot-spots' on PCSK9's surface can accelerate drug discovery in this area.
The project aims to design hybrid peptides that target PCSK9 at two stages: production and receptor recognition. These dual-mode inhibitors are expected to show higher potency and long-term efficacy than those acting through only one mechanism. The compounds will be subjected to biological evaluation to assess their ability to inhibit PCSK9 expression and LDLR interaction. |