Targeting Necrosis: Elastase-like Protease Inhibitors Curtail Necrotic Cell Death Both in Vitro and in Three in Vivo Disease Models

Boris Khalfin, Alexandra Lichtenstein, Amnon Albeck, Ilana Nathan

Research output: Contribution to journalArticlepeer-review

Abstract

Necrosis is the main mode of cell death, which leads to multiple clinical conditions affecting hundreds of millions of people worldwide. Its molecular mechanisms are poorly understood, hampering therapeutics development. Here, we identify key proteolytic activities essential for necrosis using various biochemical approaches, enzymatic assays, medicinal chemistry, and siRNA library screening. These findings provide strategies to treat and prevent necrosis, including known medicines used for other indications, siRNAs, and establish a platform for the design of new inhibitory molecules. Indeed, inhibitors of these pathways demonstrated protective activity in vitro and in vivo in animal models of traumatic brain injury, acute myocardial infarction, and drug-induced liver toxicity. Consequently, this study may pave the way for the development of novel therapies for the treatment, inhibition, or prevention of a large number of hitherto untreatable diseases.

Original languageEnglish
Pages (from-to)1510-1523
Number of pages14
JournalJournal of Medicinal Chemistry
Volume64
Issue number3
DOIs
StatePublished - 11 Feb 2021

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