Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy

Abstract

The energetics of the folding of a single-stranded nucleic acid into a stem-loop structure depend on both the composition and order of its bases. Composition tends to reflect genome-wide evolutionary pressures. Order better reflects local pressures. Base order is likely to be conserved when encoding a function critical for survival. The base order-dependent component of the folding energy has shown that a highly conserved region in HIV-1 genomes associates with an RNA structure. This corresponds to a packaging signal that is specifically recognized by the nucleocapsid domain of the Gag polyprotein. Long viewed as a potential HIV-1 "Achilles heel," the signal can be targeted by a recently described antiviral compound (NSC 260594) or by synthetic oligonucleotides. Thus, a conserved base-order-rich region of HIV-1 may facilitate therapeutic attack. Although SARS-CoV-2 differs in many respects from HIV-1, the same technology displays regions with a high base order-dependent folding energy component, which are also highly conserved. This indicates structural invariance (SI) sustained by natural selection. While the regions are often also protein-encoding (e.g. NSP3, ORF3a), we suggest that their nucleic acid level functions, such as the ribosomal frameshifting element (FSE) that facilitates differential expression of 1a and 1ab polyproteins, can be considered potential "Achilles heels" for SARS-CoV-2 that should be susceptible to therapies like those envisaged for AIDS. The region of the FSE scored well, but higher SI scores were obtained in other regions, including those encoding NSP13 and the nucleocapsid (N) protein.