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Peptidomimetic fluoromethylketone rescues mice from lethal endotoxic shock
S R Grobmyer1, R C Armstrong, S C Nicholson
1Department of Surgery, Weill Medical College of Cornell University, New York, New York 10021, USA.
Background:
Septic shock is a leading cause of mortality in intensive care units. No new interventions in the last 20 years have made a substantial impact on the outcome of patients with septic shock. Identification of inhibitable pathways that mediate death in shock is an important goal.
Materials And Methods:
Two novel caspase inhibitors, (2-indolyl)-carbonyl-Ala-Asp-fluoromethylketone (IDN 1529) and (1-methyl-3-methyl-2-indolyl)-carbonyl-Val-Asp-fluoromethylketone (IDN 1965), were studied in a murine model of endotoxic shock.
Results:
IDN 1529 prolonged survival when given before or up to 3 hr after high-dose LPS (p < 0.01) and increased by 2.2-fold the number of animals surviving longterm after a lower dose of LPS (p < 0.01). Despite its similar chemical structure, IDN 1965 lacked these protective effects. Both compounds inhibited caspases 1, 2, 3, 6, 8, and 9, and both afforded comparable reduction in Fas- and LPS-induced caspase 3-like activity and apoptosis. Paradoxically, administration of IDN 1529 but not IDN 1965 led to an increase in the LPS-induced elevation of serum cytokines related directly (IL-1beta, IL-18) or indirectly (IL-1alpha, IL-1Ra) to the action of caspase 1.
Conclusions:
A process that appears to be distinct from both apoptosis and the release of inflammatory cytokines is a late-acting requirement for lethality in endotoxic shock. Inhibition of this process can rescue mice even when therapy is initiated after LPS has made the mice severely ill.
Insights
Novel caspase inhibitors show promise in treating septic shock. IDN 1529 prolonged survival in mice by inhibiting a key lethality pathway, even when administered late.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Septic shock is a major cause of intensive care unit mortality.
- Current treatments for septic shock have limited efficacy.
- Identifying new therapeutic targets is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the efficacy of two novel caspase inhibitors, IDN 1529 and IDN 1965, in a murine model of endotoxic shock.
- To explore the mechanisms by which these inhibitors affect cell death pathways and cytokine release.
Main Methods:
- Administration of IDN 1529 and IDN 1965 to mice subjected to lipopolysaccharide (LPS)-induced endotoxic shock.
- Assessment of survival rates, caspase activity, apoptosis, and serum cytokine levels.
- In vitro inhibition of various caspases by the tested compounds.
Main Results:
- IDN 1529 significantly prolonged survival in mice, even when administered up to 3 hours after LPS exposure.
- IDN 1965, despite a similar chemical structure, did not show protective effects.
- Both compounds inhibited multiple caspases and reduced apoptosis, but only IDN 1529 increased LPS-induced serum cytokines related to caspase 1 activity.
Conclusions:
- A late-acting lethality pathway in endotoxic shock, distinct from apoptosis and cytokine release, can be targeted for therapeutic benefit.
- IDN 1529 demonstrates potential as a therapeutic agent for septic shock by inhibiting this pathway.
- Therapy for septic shock may be effective even when initiated after disease progression.
