心力衰竭的细胞分子生物学基础：PKC激活和心力衰竭—英文课件.pptVIP

Wei DUANSchool of MedicineDeakin UniversityMelbourne, Australia Heart Failure in Australia The prevalence of heart failure in Australia is ~6.3% . The heart failure prevalence is 10% in people aged over 65 years (this population will double over the next 50 years in Australia). wo Nature Medicine, 10:239,2004 Most available kinase inhibitors are ATP-binding site analogues Study of the function of C-terminus of PKC-alpha The last 10 amino acid residues are essential for the catalytic competence of PKC-alpha The critical role of the very C-terminus of PKC-a in the activation of MAPK Targeting “intrinsically disordered segment” instead of “druggable pocket”. Proof-of-principle data Aptamers (from Latin aptus, means “fitting”) Nucleic Acids Base Pairing SELEX: Systemic Evolution of Ligands by Exponential enrichment. Develop Aptamers Targeting the very C-terminus of PKC ? From Aptamer to Small Molecule Drugs: Aptamer-guided HTS Source of Chemical Libraries Commercial sources (free of royalty) --NCI (/docs/misc/available_samples/dtp_indsamples.html) Structural Diversity Set, version 1 (1,991 compounds) Structural Diversity Set, version 2 (1,986 compounds) Mechanistic Diversity Set (879 compounds) Open Collection 1 (90,000 compounds) Open Collection 2 (10,000 compounds) --ChemDiv () --ChemBridge Corporation (/chembridge/) Partnership with pharmas Partnership with academia MOLECULAR LIBRARIES SCREENING CENTERS NETWORK (Established in 2004) 9 Centers Molecular Medicine for Heart Diseases * * Molecular Medicine for Heart Failure Isozyme-specific Modulation of PKC? Stages of heart failure from Goldman: Cecil Medicine, 23rd ed Effusion from congestive heart failure from Mason: Murray Nadels Textbook of Respiratory Medicine, 4th ed Molecular Cell Biology underlying heart failure: PKC Activation and Heart Failure Circulation Research. 2007;101:195 J. Clin. Invest., 115:527,2005 Activation of PKC? and Heart Failure PKC? is activated by Gq/G11 -PLC? -IP3-SR