Finding an informed approach to oligonucleotide ligand screening to enable antiviral materials

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

PART 1: Nontechnical Abstract: As bio-inspired ligands for various biological targets, aptamers present key promising advantages over antibodies including their low immunogenicity, animal-free generation, reversible denaturation, and longer shelf-life. Moreover, while research and financial investments in therapeutic antibody development and manufacturing have clearly overshadowed that of aptamers, oligonucleotide ligands still hold promising potential as advantageous targeting and even inhibition agents for challenging viral targets whose rapid spread and mutation capabilities can unfortunately outpace traditional therapeutic developments. In the absence of a priori rules to identify potential binding motifs within a self-hybridized oligonucleotide for a non-nucleotide target, finding the right aptamer (or set of aptamers) for a particular target is a daunting search problem, much like finding the right move in a game of Chess or Go, largely because the candidate sequence space is staggeringly large. Thus, in the absence of any chemical guidelines, researchers traditionally choose instead to simply maximize the sequence diversity among candidate aptamers by employing screening libraries consisting of large heterogeneous populations (~109 or more) of random DNA or RNA sequence members in a resource-intensive screening process called SELEX (Systematic Evolution of Ligands by EXponential Enrichment). Here, the goal of the proposed work is to develop a pipeline of candidate DNA aptamers for spike protein. To undertake this ambitious goal for this pilot project we will pioneer an integrated experimental and informatics approach to rapidly and reliably identify DNA oligonucleotide ligands from informed, designer libraries for a viral protein target called the spike protein. PART 2: Technical Abstract: Research and financial investments in therapeutic antibody development and manufacturing have clearly overshadowed that of lesser known, oligonucleotide-based ligands called aptamers. Aptamers, on the other hand, hold promising potential as advantageous targeting and even inhibition agents for challenging viral targets whose rapid spread and mutation capabilities can unfortunately outpace traditional therapeutic developments. In the absence of design rules, finding the right aptamer (or set of aptamers) for a particular target is a daunting search problem, much like finding the right move in a game of Chess or Go, largely because the candidate sequence space is staggeringly large. Thus, in the absence of any chemical guidelines, researchers traditionally choose instead to simply maximize the size (~109 or more different sequences) of screening libraries in a resource-intensive, evolutionary screening process called SELEX (Systematic Evolution of Ligands by EXponential Enrichment). To overcome these challenging technical and scientific bottlenecks inherent to this popular aptamer screening platform, we propose to pioneer an integrated experimental and informatics approach to rapidly and reliably identify DNA oligonucleotide ligands from designer libraries for a viral protein target called the spike protein. The proposed integrated experimental/computational aptamer discovery approach is intentionally adaptable using a “lessons-learned” approach to pave the aptamer discovery pathway for viral targets, particularly as viral strains readily mutate. This work will offer unique, multidisciplinary student training opportunities in the experimental and computational aspects of the work. If successful the PIs believe this pilot project will lay the fundamental groundwork for future accelerated bio-inspired ligand discovery to enable desirable bioactivity of materials systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.