As the world braces to enter its fourth year of the coronavirus
disease 2019 (COVID-19) pandemic, the need for accessible and effective
antiviral therapeutics continues to be felt globally. The recent surge
of Omicron variant cases has demonstrated that vaccination and prevention
alone cannot quell the spread of highly transmissible variants. A
safe and nontoxic therapeutic with an adaptable design to respond
to the emergence of new variants is critical for transitioning to
the treatment of COVID-19 as an endemic disease. Here, we present
a novel compound, called SBCoV202, that specifically and tightly binds
the translation initiation site of RNA-dependent RNA polymerase within
the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome,
inhibiting viral replication. SBCoV202 is a Nanoligomer, a molecule
that includes peptide nucleic acid sequences capable of binding viral
RNA with single-base-pair specificity to accurately target the viral
genome. The compound has been shown to be safe and nontoxic in mice,
with favorable biodistribution, and has shown efficacy against SARS-CoV-2 in vitro. Safety and biodistribution were assessed using
three separate administration methods, namely, intranasal, intravenous,
and intraperitoneal. Safety studies showed the Nanoligomer caused
no outward distress, immunogenicity, or organ tissue damage, measured
through observation of behavior and body weight, serum levels of cytokines,
and histopathology of fixed tissue, respectively. SBCoV202 was evenly
biodistributed throughout the body, with most tissues measuring Nanoligomer
concentrations well above the compound K
D of 3.37 nM. In addition to favorable availability to organs such
as the lungs, lymph nodes, liver, and spleen, the compound circulated
through the blood and was rapidly cleared through the renal and urinary
systems. The favorable biodistribution and lack of immunogenicity
and toxicity set Nanoligomers apart from other antisense therapies,
while the adaptability of the nucleic acid sequence of Nanoligomers
provides a defense against future emergence of drug resistance, making
these molecules an attractive potential treatment for COVID-19.