Receptors, Ligands, and Catalysts on Demand using Expanded Genetic Alphabets

DESCRIPTION provided by applicant Technology to deliver molecules andquot on demandandquot that bind to targets or catalyze reactions of a technologistandapos s choosing would have enormous commercial value in research manufacturing and medicine Thus this has been a andquot holy grailandquot of molecular science for a half century Even today chemical theory is inadequate to support de novo design of receptors ligands or catalyst having useful affinities or catalytic power Thus many have sought to bring Darwinism into the laboratory Here the hope is to re create under control of a technologist the evolutionary processes that create the powerful receptors ligands and catalysts found in Nature One approach to create laboratory Darwinism was begun by Gold Szostak and others to exploit the intrinsic ability of natural DNA and RNA collectively xNA molecules to direct their own replication These and others developed the technology that we andquot laboratory in vitro evolutionandquot LIVE which places libraries of xNA molecules under laboratory selection pressure to extract those that bind to targets Unfortunately because natural xNA molecules have only four building blocks with few functional groups they have low information density ambiguous folding and little intrinsic functional power and therefore have seen little commercial use Using synthetic biology and a second generation artificially expanded genetic information system AEGIS FfAME and Firebird scientists have created a fundamental breakthrough in LIVE technology This involves adding initially two but potentially up to eight additional nucleotides to standard xNA These can carry not only functionality found in natural amino acids but functionality in addition to that seen in natural proteins including antibodies which provide current state of the art technology for creating binding molecules To lay the grounds for this commercialization proposal we used AEGIS LIVE to create AEGIS aptamers for customers who were seeking molecules that bind specifically to breast and liver cancer cells This grant will fund the next logical step commercializing AEGIS LIVE via two overlapping business models a A custom research collaboration model where Firebird staff provide an AEGIS LIVE service at a fee to generate receptors ligands and catalysts that are chosen by customers and clients b A product generation model where Firebird uses AEGIS LIVE to generate receptors ligands and catalysts of its own choosing as commercial products in their own right Phase will perform AEGIS LIVE that for the first time targets a specific defined molecule glypican a protein that is key to the lethality of many cancers AEGIS LIVE will be compared with a standard LIVE without AEGIS as well as antibodies for the same protein target AEGIS aptamers will be delivered to our customer Dr Chen Liu at University of Florida to support his liver cancer research As well as generating AEGIS aptamers having value in their own right this work will demonstrate the flexibility of AEGIS LIVE develop supporting infrastructure and launch commercialization of technology that NIH referees note is andquot a game changerandquot PUBLIC HEALTH RELEVANCE Technology that delivers receptors and ligands with rapid turn around will ultimately capture markets worth tens of billions of dollars for therapeutics diagnostics and environmental surveillance among others Using synthetic biology and artificially expanded genetic systems researchers in the two collaborating organizations have created a fundamental breakthrough in this technology by combining chemical andquot coarse designandquot with laboratory evolution andquot fine tuningandquot This breakthrough has been proven through published work that provides detailed recipes to generate receptors that bind specifically to breast and liver cancer cells This project will now commercialize this technology Its proof of concept Phase will for the first time generate receptors that bind to defined molecular targets involve in cancer treatment These are commercial products in their own right but also will serve as demonstrations of the power of this technology that will attract contract research