Inhibiting the Inflammasome: A Chemical Perspective

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• 作者：Alex G. Baldwin ; David Brough ; Sally Freeman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：59
• 期：5
• 页码：1691-1710
• 全文大小：1104K
• 年卷期：Alex G. Baldwin
  received his B.Sc. in Biological and Medicinal Chemistry from the University of Exeter, U.K., in 2013. Alex is the recipient of two scholarships and nine awards, including the Society of Biology Top Student Award and President’s Doctoral Scholar Award. Alex is currently studying for his Ph.D. in the Manchester Pharmacy School at the University of Manchester. Alex’s current work focuses on the design, synthesis, and evaluation of novel inhibitors of the NLRP3 inflammasome.
  David Brough
  received his B.Sc. in Biosciences and Chemistry (1999) from the Robert Gordon University, Aberdeen, and Ph.D. in Biological Sciences (2002) from the University of Manchester. Following postdoctoral positions at the Universities of Cambridge, and then Manchester, David was awarded a Fellowship from the Wellcome Trust (2008) to establish research independence. Since 2013, David is a Lecturer at the University of Manchester.
  Sally Freeman
  received her B.Sc. in Chemistry (1982) and Ph.D. (1985) from the Department of Chemistry at the University of Leicester, U.K., prior to postdoctoral studies with Professor Jeremy Knowles at Harvard University. Sally was a lecturer in the Aston Pharmacy School, Aston University, from 1987, moving to the Manchester Pharmacy School at the University of Manchester in 1995, where she is currently a Reader in Medicinal Chemistry.
• ISSN：1520-4804

文摘

Inflammasomes are high molecular weight complexes that sense and react to injury and infection. Their activation induces caspase-1 activation and release of interleukin-1β, a pro-inflammatory cytokine involved in both acute and chronic inflammatory responses. There is increasing evidence that inflammasomes, particularly the NLRP3 inflammasome, act as guardians against noninfectious material. Inappropriate activation of the NLRP3 inflammasome contributes to the progression of many noncommunicable diseases such as gout, type II diabetes, and Alzheimer’s disease. Inhibiting the inflammasome may significantly reduce damaging inflammation and is therefore regarded as a therapeutic target. Currently approved inhibitors of interleukin-1β are rilonacept, canakinumab, and anakinra. However, these proteins do not possess ideal pharmacokinetic properties and are unlikely to easily cross the blood–brain barrier. Because inflammation can contribute to neurological disorders, this review focuses on the development of small-molecule inhibitors of the NLRP3 inflammasome.