FIREBIRD BIOMOLECULAR SCIENCES LLC — Department of Health and Human Services STTR Phase I: NIGMS

Description

Commercial Polymerases to Create Receptors Ligands and Catalysts on Demand Firebird Biomolecular Sciences LLC University of Texas Steven A Benner Andrew D Ellington ABSTRACT Innovators at Firebird Biomolecular Sciences LLC have created several generations of an artificially ex panded genetic information system AEGIS that adds eight nucleobases that form four additional pairs Z P S B K X V J to the four natural nucleotides that form the standard G C and A T pairs AEGIS components carry functional groups not found in natural DNA and RNA collectively xNA NH SH COOH as well as some not found in any natural biopolymer e g B OH and ONH Thus AEGIS is a new kind of polymer replicable evolvable and adaptable like DNA but also having much of the functional potential of proteins In DNA AEGIS has been remarkably successful Six letter GACTSB AEGIS DNA enables two FDA approved products that measure hepatitis and HIV viral loads here the ability of AEGIS DNA to pair only with AEGIS DNA and not to background xNA orthogonality allowed these products to earn ca $ million each year in their ten year life The orthogonality of GACTZP AEGIS DNA as well as its ability to be replicated with high fidelity by DNA polymerases are today exploited in diagnostics and surveillance for respiratory disease viruses common and exotic arboviruses in mosquitoes noroviruses and coronaviruses e g SARS MERS Firebird now sees the opportunity to expand its product portfolio from AEGIS DNA to include AEGIS RNA Its scientists recently reported large scale syntheses of AEGIS RNA triphosphates and phosphoramidites these are now sold in its catalog Further Firebird scientists have shown that T RNA polymerase makes AEGIS RNA from AEGIS DNA although inefficiently and found reverse transcriptases that make AEGIS DNA from AEGIS RNA in both six and eight letter versions e g GACTSBZP These are leads for the proposed research RNA is well known to have a richer set of folds and more intrinsic potential to serve as receptors and ligands aptamers a term and technology invented by the subcontractor Functionalized AEGIS RNA will thus likely be better than AEGIS DNA in these biomolecules Functionalized AEGIS RNA will also have enhanced value in laboratory in vitro evolution LIVE experiments to create receptors ligands and catalysts on demand Should this vision be realized it will create a revolutionary transformation of diagnostics and therapeutics This vision requires better RNA polymerases and reverse transcriptases While Firebird could undertake their development in house advances in the Ellington laboratory at the University of Texas suggests that collabora tion would achieve this goal faster Ellington has already created directed evolution platforms to give T RNA polymerases and thermostable reverse transcriptases that accept unnatural but not AEGIS nucleotides This collaboration will apply those platforms to create enzymes that interconvert AEGIS DNA and AEGIS RNA The enzymes themselves will be commercial products they will also however support LIVE with this evolvable functionalized AEGIS biopolymer Phase will show the feasibility of using Ellington s platforms to create these enzymes Given feasibility the platforms will be applied in Phase to complete letter AEGIS alphabets Commercial Polymerases to Create Receptors Ligands and Catalysts on Demand Firebird Biomolecular Sciences LLC University of Texas Steven A Benner Andrew D Ellington NARRATIVE This project will generate for sale as well as for internal use at Firebird and the University of Texas RNA polymerases and reverse transcriptases that interconvert DNA and RNA built from a new type of biopolymer one that adds eight nucleobases that form four additional pairs Z P S B K X V J to the four natural nucleotides which form two natural pairs in the double helix G C and A T These polymerases acting with this artificially expanded genetic information system AEGIS have biomedical value as a result of their ability to create by laboratory in vitro evolution AEGIS RNA products that serve as receptors ligands and catalysts on demand AEGIS DNA and its distinct properties already have supported hundreds of millions of dollars worth of diagnostics products The RNA products that this research enableswill be used not only in diagnostics and therapy but also as research tools to help understand the newly discovered roles for RNA in natural and diseased biology