Drugging the SARS-CoV-2 Genome
SARS-CoV-2, the virus that causes COVID, has killed millions and wreaked havoc on global economies. The enormity of the COVID pandemic has spurred unprecedented scientific advancements in a fight to combat the virus. Within a year, treatment options such as Gilead’s remdesivir and preventative measures such as Pfizer and Moderna’s mRNA vaccines have been developed, tested, and implemented. While these pharmaceuticals have helped make immense progress in combatting the pandemic, research into SARS-CoV-2 and related viruses is ongoing. The development of new drugs and therapeutic modalities will be critical not only to ending the current pandemic, but also ameliorating the effects of future viral diseases.
SARS-CoV-2 and related viruses infect their host cells by introducing viral RNA into the cell. The RNA is then translated into proteins by native cell structures, and the resultant proteins work to replicate the viral genome and build new copies of the virus. Recently, researchers from the Scripps Research Institute in California have published a paper outlining methods of targeting a frameshift element in the SARS-CoV-2 genome to interfere with viral replication (Haniff et al.). RNA is translated into a protein through a molecular machine called a ribosome, which reads the RNA three bases at a time. Frameshift elements in the viral genome are crucial to ensure the ribosome reads the correct groupings of three bases. Specifically, the researchers targeted part of a frameshift element called an attenuator hairpin, a small bulging structure of RNA. They screened a library of curated molecules with known RNA binding activity to find hits that bound specifically to the SARS-CoV-2 attenuator hairpin (Haniff et al.).
The researchers further narrowed their initial hits by testing them against an engineered SARS-CoV-2 genome analogue (Haniff et al.). Their analogous RNA system had two RNA sequences that each produced a fluorescent protein as well as the SARS-CoV-2 frameshift element. If the frameshift element was working correctly, both fluorescent proteins could be translated. However, if the frameshift element was inhibited, only one fluorescent protein would be produced. Ultimately, the researchers found one molecule that specifically inhibited the frameshift element without interfering with the RNA more broadly. Furthermore, the compound had no effect when tested on a similar system that used the SARS-CoV frameshift element, a related but distinct structure (Haniff et al.).
With a validated target binder discovered, the researchers sought to increase the potency of their potential drug by converting it into a so-called RIBOTAC (or Ribonuclease Targeting Chimera) (Haniff et al.). RIBOTACs act as a bridge between their target RNA and a ribonuclease, a class of enzymes that destroy RNA. The scientists attached their RNA-binding molecule to a known ribonuclease-recruiting molecule through a short chemical linker. In the fluorescent protein system, the scientists found that their RIBOTAC reduced production of both fluorescent proteins, which are the products of RNA translation; this finding is consistent with the hypothesis that the entire RNA was being destroyed. Furthermore, the potency of the RIBOTAC was increased by at least one order of magnitude compared to the RNA binder alone (Haniff et al.).
While therapeutics such as RIBOTACs (and a related class called PROTACs) are few and far between in the clinical setting, they hold immense promise for the future of rational drug design. Not only do they have the potential to act as catalytic drugs, destroying many copies of their target, but they also boast the wonderful simplicity of recruiting our natural cellular machinery to create a therapeutic effect. Certainly, such innovative methods will be necessary to advance our fight against infectious disease.
Work Cited
Haniff, Hafeez S., et al. “Targeting the SARS-CoV-2 RNA Genome with Small Molecule Binders and Ribonuclease Targeting Chimera (RIBOTAC) Degraders.” ACS Central Science, vol. 6, no. 10, 2020, pp. 1713–1721., doi:10.1021/acscentsci.0c00984.
Last Fact Checked on May 24th, 2021.