Preclinical Development of a Novel Small Molecule Drug for Sepsis

PROJECT DESCRIPTIONThis STTR Phase I proposal is intended to demonstrate the feasibility of developing tanshinone small molecule analogTSAas an effective and safe small molecule therapy for patients with sepsis and septic shockIn the USmore than one million people develop sepsis every yearYetno effective anti sepsis treatment exists other than antibiotics and supportive careWe have discovered that high mobility group boxHMGBis a pivotal proinflammatory mediator released by macrophages during sepsisWe have also discovered that tanshinone IIA sodium sulfonatein high dosesdecreased circulating levels of HMGBand improved the survival rate in the endotoxemia and cecal ligation and puncture models of sepsisTo further enhance the solubility and the binding affinity for HMGBwe generate TSAby opening up tanshinone s orthobenzoquinone and introducing a carboxylic groupThe affinity of TSAfor HMGBisfold higher than that of the tanshinone IIA sodium sulfateTSAalso potently inhibits the release of proinflammatory cytokines and chemokines known to aggravate and perpetuate inflammation in sepsisBased on these preliminary studieswe hypothesize that TSAcan be developed as an effective and safe therapeutic agent to treat patients with sepsis and septic shockTo advance TSAtowards its ultimate clinical usewe will identify its most effective dose and therapeutic window to attenuate organ injury and improve survival in an animal model of sepsisWe will then determine TSAs safety and pharmacokinetic profileThese proposed studies will provide critical feasibility information to further develop TSAas an HMGBsuppressing agent to treat sepsisOur ultimate goal is to obtain commercial utilization of TSAas a novel and effective treatment for patients with sepsis and septic shock