Identification of indothiazinone as a natural antiplatelet agent. (25th May 2017)

• Record Type: Journal Article
• Authors: Yang, Chansik; Kwon, Sugyeong; Kim, Se‐Jong; Jeong, Minseon; Park, Ji‐Young; Park, Dongeun; Hong, Soon Jun; Jung, Jong‐Wha; Kim, Chungho
• Is Part Of: Chemical biology & drug design. Volume 90:Number 5(2017)
• Page Start: 873
• Page End: 882
• Publication Date: 2017-05-25
• Subjects: antiplatelet drug -- indothiazinone -- integrin αIIbβ3 -- platelet -- talin; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13008
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract : Cardiovascular disease, which is caused by unregulated platelet aggregation, is one of the main causes of deaths worldwide. Many studies have focused on natural products with antiplatelet effects as a safe alternative therapy to prevent the disease. In this context, an in‐house chemical library was screened to find natural products capable of inhibiting the interaction between platelet integrin αIIbβ3 and fibrinogen, which is an essential step in platelet aggregation. On the basis of the screening results, indothiazinone, an alkaloid found in microbial cultures, was identified as a potential antiplatelet agent. Specifically, indothiazinone treatment significantly inhibited the binding of fibrinogen to Chinese hamster ovary cells expressing integrin αIIbβ3. It also restricted thrombin‐ and adenosine diphosphate‐dependent spreading of human platelets on a fibrinogen matrix. More importantly, surface plasmon resonance and molecular dynamics studies suggested that indothiazinone suppressed talin‐induced activation of integrin αIIbβ3 presumably by inhibiting talin–integrin interaction. In conclusion, these results suggest that indothiazinone can be used as a lead compound for the development of antiplatelet drugs with a novel mode of action. Abstract : Indothiazinone, a natural product from myxobacteria, was shown to inhibit agonist‐induced platelet spreading by suppressing talin‐mediated integrin αIIbβ3 activation. This study also shows that indothiazinone can be used as a lead compound in the development of antiplatelet drugs with a novel mode of action.