SRI Biosciences, a division of SRI International, has been awarded a $10 million contract under a DARPA program to reimagine how proteins are constructed and to develop novel medicines and diagnostics as countermeasures to chemical and biological threats.
The new contract is part of DARPA’s Folded Non-Natural Polymers with Biological Function program, known as Fold F(x). The initial goal of the program is to develop biologically active non-natural polymers that are structurally similar to naturally occurring proteins, but without their limitations, such as sensitivity to heat denaturation or chemical degradation.
To develop the new polymers, SRI is combining its expertise in medicinal chemistry and biopolymer design with a breakthrough approach to screening vast numbers of compounds. The novel polymers are being made from entirely new types of monomer structures based on drug-like scaffolds with high functional group density.
SRI’s compound screening innovation is based on its proprietary Fiber-Optic Array Scanning Technology (FASTcell). Originally developed to identify circulating tumor cells in a blood sample, FASTcell can distinguish a single tumor cell among tens of millions of healthy ones in a few minutes. With DARPA support, SRI is expanding this technology to screen 25 million compounds in just one minute.
“Our goal is to develop a method that can enable rapid, large-scale responses to a bioterrorism threat or an infectious disease epidemic,” said Peter Madrid, Ph.D., program director in SRI Biosciences’ Center for Chemical Biology and co-principal investigator and leader of the chemistry effort of the project. “We are looking for non-natural polymers to detect or neutralize identified chemical or biological threats. Once we find potent molecules, we will be able to produce them at mass on a large scale.”
The overall goal of the Fold F(x) program is to expand on the utility of proteins and DNA, and to overcome their limitations by re-engineering their polymer backbones and side chain diversity—creating new molecules with improved functionality such as stability, potency and catalytic function in environments usually hostile for biopolymers.
The knowledge to design new functional molecules from first principles doesn’t exist yet. The alternative is to synthesize enormous libraries of non-natural polymers and screen for sequences that have a desired action. Finding a single effective compound, such as one that can block a virus, may require screening hundreds of millions of compounds.
“We are taking a full departure from how nature does things to come up with new ways of mimicking protein function in a highly tailored and controlled way,” said Nathan Collins, Ph.D., executive director of SRI Biosciences’ Discovery Sciences Section and principal investigator of SRI’s Fold F(x) project. “Our breakthrough has been to adapt SRI’s FASTcell technology to screen libraries of non-natural polymers. It’s very exciting to be doing such novel research.”
Initially the program will focus on screening massive numbers of non-natural polymers for potential uses against security threats. As a proof of concept, the team will design, synthesize and screen chemically unique libraries of 100 million non-natural polymers for activity against a variety of agents, including toxins such as ricin and viruses such as the H1N1 bird flu strain of influenza.
As the program evolves it may progress to include a range of possibilities, such as how to synthesize molecules to fold such that they emit light, have enhanced levels of strength or elasticity, or store power.