ABSTRACT: Our overall objective is to develop a novel class of outpatient therapeutics targeting highly- conserved RNA structures in the genomes of SARS-CoV-2 and other respiratory viruses of pandemic potential. Using influenza A virus (IAV) as a proof-of-concept, we previously showed that: 1) adding high-resolution RNA secondary structure target information into the design of antisense oligonucleotide (ASO)-based therapeutics can greatly enhance antiviral efficacy over simply targeting conserved primary sequence, as can incorporating into the ASO design the ability to recruit RNase H to the target site; 2) a single intranasal dose of a highly stable, locked nucleic acid (LNA) ASO designed against a universally conserved RNA structure provides 100% survival when given 14 days before, or 3 days after a lethal IAV inoculum; and 3) no resistance to our LNA has been selectable. Applying a similar approach, via a process we now term “programmable antivirals,” to SARS-CoV-2, we 1) rapidly identified highly conserved RNA structures; 2) designed LNAs against these targets and showed that cryo-electron microscopy (cryoEM) of a structure led to improved LNA design; 3) demonstrated that our lead LNAs have compelling in vitro and in vivo efficacy against reference and clinical isolates, including virus harboring mutations that reduce vaccine efficacy (e.g. delta variant). Complementarily, we have pioneered a novel strategy, named “Inforna,” to design small molecules that selectively bind viral RNA structures and inhibit noncoding RNAs involved in human genetic diseases and RNA viruses, including SARS-CoV-2, some with activities in the nM and pM range. The small molecules can be modified to recruit an endogenous nuclease, akin to the RNase H-induced degradation by LNA ASOs. We term this type of small molecule a “ribonuclease targeting chimera (RIBOTAC).” We now hypothesize that: 1) our lead LNA molecules—including one targeting a RNA structure common to SARS-CoV-1 and MERS-CoV—already represent ideal development candidates; 2) the LNAs’ antiviral potency can be further enhanced; 3) the resulting LNAs will have a high barrier to the development of resistance and be broadly active against wild-type and vaccine-resistant strains; 4) Inforna can help design small molecules and RIBOTACs against our identified target structures; 5) our therapeutics are combinable with other anti-SARS-CoV-2 agents; and 6) analogous approaches can be rapidly applied against RNA viruses of pandemic concern. We will test these hypotheses by: 1) selecting a lead (and back up) LNA anti- SARS-CoV-2 therapeutic from “second generation” LNAs informed by optimizations around current leads and cryoEM structures of their targets; 2) advancing the lead LNA therapeutic towards the clinic by expanding the in vitro and in vivo virology data package and performing requisite CMC and IND-enabling activities; 3) identifying and optimizing small molecules and RIBOTACs against the same SARS-CoV-2 RNA targets; and 4) identifying, characterizing, and targeting conserved candidate RNA structure targets in other RNA viruses of pandemic potential and developing programmable LNA and small molecule/RIBOTAC therapeutics against them.