High Throughput-driven Discovery and Ruggedization of Hybrid Bio-abiotic Systems for OPNA Degradation
Abstract
Biocatalytic degradation of organophosphate nerve agents (OPNA) with enzymes is a powerful method for decontamination that is unfortunately limited by enzyme instability and non-universal specificity. This proposal builds on exciting recent advances in the identification of novel nucleophiles capable of hydrolyzing OPNAs, including our own work with such nucleophiles in the degradation of Sarin, by using high throughput screening (HTS) to identify yet more powerful OPNA-degrading nucleophiles. Almost all of these first-generation nucleophiles are stoichiometric reagents. In biology, amino-acid based nucleophiles that interact with enzyme bound substrates are regenerated in a catalytic cycle. We are particularly focused on understanding how the correct presentation of a nucleophile on an OPNA-binding core can build next-generation catalysts. We will rely on our ongoing work in protein-polymer structure-function-motion relationship development to guide rationally how to display the HTS-derived nucleophiles. We will rationally design and then build OPNA-binding proteins that contain abiotic nucleophiles using polymer-based protein engineering (PBPE). We have already demonstrated the stabilizing potential of PBPE and its use to display OPNA reactive nucleophiles. In the proposed work, we will bring these two key features of a robust system together. Bio-abiotic hybrids of nucleophilic polymers with OPNA binding proteins have the potential to deliver desired changes in stability, while transforming serine-hydrolases, such as cholinesterases, from stoichiometric into catalytic OPNA scavengers under environmentally stressful conditions. The ubiquitous property of all cholinesterases (ChE), to bind G- and V-OPNAs and their stereoisomers at high affinity, will be utilized to transform the enzyme into a universal catalyst for all OPNAs. In our Trojan Horse approach the target of the nerve agent will become the means through which the nerve agent is destroyed. We anticipate that the design and discovery of the proposed novel bio-abiotic matrices will offer significant improvements in non-corrosive decontamination.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- HDTRA11810028
Entities
People
- Alan J. Russell
Organizations
- Defense Threat Reduction Agency
- Massachusetts Institute of Technology