New Therapeutic Agents for Organophosphorus Nerve Agents
Abstract
This proposal seeks to develop countermeasures to mitigate the toxic effects of a major class of chemical weapons of mass destruction, organophosphate nerve agents (OPNAs). Currently used antidotes are only moderately effective for acute OPNA toxicity because they do not enter the central nervous system (CNS) locations where OPNAs manifest their toxicity, and OPNA survivors still face long-term neurological damage. To counteract the acute toxicity, we will first develop chemical switches to transiently perturb the structures of currently used anti-dotes. The resulting compounds are expected to permeate the blood brain barrier (BBB). Second, we will develop antidotes that will restore the OPNA-inhibited acetylcholine esterase (AChE) more effectively. To combat the long-term neurological effects, we will deploy a mitochondrial-targeted therapeutic that passes the BBB, enriches in mitochondria in neurons and glia cells, and prevents neurological damage caused by OPNAs. At a molecular level, the nitroxide-containing lead structures, XJB-5-131 and JP4-039, prevent the reactive oxygen species-induced oxidative degradation of a crucial membrane lipid component, cardiolipin. After pharmacokinetics analysis of optimized development candidates, we will study their in vivo efficacy to protect against paraoxon, a validated model OPNA. Mice have been selected for this preclinical study because they have previously been used for the development of countermeasures to AChE inhibition and they require smaller quantities of synthesized compounds than guinea pig models. We are aware of the higher relevance of guinea pig models to humans and will use guinea pigs after we opti-mize countermeasure efficacy and prioritize our lead structures in mice
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 13, 2016
- Source ID
- HDTRA11610041
Entities
People
- Kazunori Kolde
Organizations
- Defense Threat Reduction Agency
- University of Pittsburgh