Compounds modulating frameshifting efficiency for antiviral therapy against HIV-1, SARS-CoV-2 and alphaviruses

Scientists from the Max-Planck-Institute for Multidisciplinary Sciences could show that FS efficiency is determined by the availability of tRNA^Leu which reads the UUA codon in cis-acting elements (slippery sites) of viral mRNAs. The tRNA^Leu(UUA) isoacceptor is rare in human cells, especially in CD4⁺ T‑lymphocytes, the primary target cells for HIV-1 infection in humans, whereas 45 % of all Leu in late expressing HIV-1 genes (including gag and pol) is encoded by this rare codon. The scientists revealed that an increase in tRNA^Leu(UUA) concentration led to a significant reduction in overall –1FS efficiency and virus propagation, thus making modulation of FS efficiency by targeting rare codon decoders an ideal approach for antiviral therapy against retroviruses and alphaviruses.

Although a variety of viral therapeutics are available, art-established therapy options often suffer from several shortcomings which include the development of resistances and adverse effects. Therapeutics based on the tRNA^Leu(UUA) which can be recognized by a ribosome and comprise the nucleotide sequence UAA or TAA and a binding site for the covalent attachment of Leu by an endogenous aminoacyl-tRNA synthetase would provide several advantages for antiviral treatment strategies. Owing to the universal conservation of the UUA codon within FS sequences across virus taxonomic categories, specific resistance mechanisms are less likely to emerge. This is of particular interest since many antiviral drug therapies that target less conserved structures suffer from the emergence of drug resistances through the development of unusual slippery sites that support different FS at levels sufficient for virus replication and pathogenicity despite the treatment.

We are now looking for a collaboration partner to further develop this project.

A PCT application was filed on July, 24th 2019: WO2020020935A1. National in EP and US.

• Korniy et al., 2019. Nucleic Acids Res. doi: 10.1093/nar/gkz202
• Chang and Wen, 2021. Comput Struct Biotechnol J. doi: 10.1016/j.csbj.2021.06.015