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# Engineering Synthetic RNAs as Interfering Anti-viral Therapeutics

Michael B. Elowitz
Professor of Biology and Bioengineering; Investigator, Howard Hughes Medical Institute; Executive Officer for Biological Engineering

Bruce A. Hay
Professor of Biology

Professors Michael Elowitz and Bruce Hay are engineering a synthetic therapeutic for SARS-CoV-2 based on defective interfering particles (DIPs), which are naturally occurring parasitic mutant virus variants that interfere with the lifecycle of co-infecting wild-type viruses. Previous work on DIP-based therapeutics has focused on ‘top-down' identification of naturally occurring DIPs. Recent advances in synthetic biology now enable a complementary bottom-up approach, in which one designs synthetic RNA molecules that can function in a manner analogous to natural DIPs, but provide the advantages of rational design and rapid design-build-test cycles. Professors Elowitz and Hay aim to design and optimize such synthetic DIPs, by focusing on two of the best-characterized molecular features of the coronavirus: sequences that interact with viral packaging components and the RNA dependent RNA polymerase, RdRp. They plan to construct synthetic RNA molecules that interact with these systems but which, like natural DIPs, are incapable of replicating and propagating on their own. These RNAs will interfere with the operation of a wild-type virus in the same cell. The team's strategy will be to independently optimize replication and packaging modules, combine them into a single synthetic DIP, and characterize its ability to inhibit pre-established or subsequent infections by wild-type virus. These efforts should establish proof of principle for the use of synthetically designed interfering particles as specific inhibitors of viral replication and packaging processes.

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