COVID-19 Research: University Of Massachusetts Study Warns Of Emerging Genomic Variants In SARS-CoV-2 Coronavirus That Could Lead To Drug Resistance

COVID-19 Research: A new research by University Of Massachusetts Medical School lead by Dr Sean P Ryder, a Professor Biochemistry and Molecular Pharmacology has demonstrated that there are numerous emerging genomic variants of the SARS-CoV-2 coronavirus and that some of these with changes on certain of parts of the structure of the genome, he warns could lead to drug resistance.


 
Dr Ryder told Thailand Medical News, “Structures with rapidly emerging variations are problematic for drug development as well, as the relatively high viral mutation rate, coupled to its potential to be edited by APOBEC and ADAR enzymes, and could lead to the rapid evolution of resistant variants.”
 
The study was just published a few hours ago on a preprint server and has yet to be peer reviewed but already a number of virologist and genomic experts are corroborating on the findings. https://www.biorxiv.org/content/10.1101/2020.05.27.120105v1.full.pdf+html
 
The research team evaluated two cohorts of SARS-CoV-2 genomic sequences to identify rapidly emerging variants within structured cis-regulatory elements of the SARS-CoV-2 genome.
 
On the whole, twenty variants are present at a minor allele frequency of at least 0.5%. Several enhance the stability of Stem Loop 1 in the 5´UTR, including a set of co-occurring variants that extend its length. One appears to modulate the stability of the frameshifting pseudoknot between ORF1a and ORF1b, and another perturbs a bi-stable molecular switch in the 3´UTR.
 
Finally, five variants destabilize structured elements within the 3´UTR hypervariable region, including the S2M stem loop, raising questions as to the functional relevance of these structures in viral replication. Two of the most abundant variants appear to be caused by RNA editing, suggesting host-viral defense contributes to SARS-CoV-2 genome heterogeneity.
 
This analysis has implications for the development therapeutics that target viral cis-regulatory RNA structures or sequences, as rapidly emerging variations in these regions could lead to drug resistance.
 
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The researchers used available data to investigate how rapidly emerging variants could impact structured cis-regulatory elements in the virus genome. These elements govern viral replication, subgenomic RNA synthesis, and translation control in other betacoronaviruses.
 
It is well known that rapidly emerging variants could enhance or dampen viral pathogenesis and overall fitness, which could affect the extent and duration of the outbreak. As such, it is critically important to understand how such variations arise, and what regions of the genome are most prone to mutation. Due to the burden of the SARS-CoV-2 outbreak, there is renewed interest in the development of novel strategies to treat betacoronavirus infections.
 
Interestingly functional RNA structures in the viral genome could provide new targets for small molecule therapeutic development. Many antibiotics work through interactions with ribosomal RNA structure, and RNA targeting small molecule drugs are currently approved or in development for a variety of infectious and genetic diseases.
 
The new SARS-CoV-2 genome has many structured elements that could be targeted, including SL1-SL4 in the 5´UTR, the frameshifting pseudoknot at the ORF1a and ORF1b boundary, and the molecular switch in the 3´UTR.
 
The research findings suggest that the hypervariable region, including the S2M structure, might be less well suited to targeted drug development. Structures with rapidly emerging variations are problematic for drug development as well, as the relatively high viral mutation rate, coupled to its potential to be edited by APOBEC and ADAR enzymes, could lead to the rapid evolution of resistant variants.
 
Also, hybridization-guided therapeutics, such as antisense oligonucleotides, small interfering RNAs, and CRISPR-derived drugs could potentially be targeted to the SARS-CoV-2 genome. Unstructured regions in noncoding regions of the viral genome make particularly compelling targets, as access will not be blocked by RNA structure or transit of the ribosome.
 
But because these strategies rely on base complementarity to achieve target specificity, rapid virus evolution could prove their Achilles’ heel. The data presented in this study identify regions less prone to variation, making them better candidates for RNA-guided therapeutics.
 
It was observed  that SL1 is prone to rapidly emerging variations is interesting, as this region is not only present on the positive strand of the viral genome, but is also found on all subgenomic RNAs (Kim et al. 2020a). Moreover, the complement to SL1 in antigenomic RNA is likely recognized by viral RNA-dependent RNA polymerase (RdRP) to produce genomic copies of the viral RNA. As such, it could make a good target for therapeutic development.
 
However, the presence of multiple variations, often in combination, makes strategies that rely upon base pairing unlikely to be effective for all virus subtypes.
 
Interestingly the diversity of variations that enhance the stability of SL1, including variations that lengthen the stem, suggests that SL1 stability is important to SARS-CoV2 replication. But if stability matters more than sequence identity, we can expect the evolution of rapid resistance to therapeutics designed to modulate SL1 stability. The bi-stable molecular switch in the 3´UTR is potentially the most compelling structure for targeted drug discovery. It is conceptually straightforward to design antisense oligonucleotides that lock the switch into one conformer or the other. Both conformers are necessary for MHV replication, and only one rapidly emerging variant of minimal consequence was identified in this region. It is likely that this switch plays a role in SARS-CoV-2 replication, as has been observed in other betacoronaviruses.
 
Further research will be necessary to assess its potential as a drug target. RNA editing appears to play a role in two rapidly emerging variations near stem loop structures in the 5´UTR. The prevalence of RNA editing of the viral genome is not known, and it remains unclear whether editing affects viral fitness or pathogenesis. It will be interesting to assess the extent of RNA editing during active infection, a task that would probably be best achieved through direct RNA sequencing. The analyses presented in this study will only improve as more sequencing data are added to available repositories. It is possible that identification of more rapidly emerging variants will clarify some of the remaining ambiguities.
 
The results presented here highlight the power of high-throughput sequencing of viral genomes to define viral cis-regulatory elements, and stand as a testament to the researchers collecting, sequencing, and sharing viral genomic data to help quell the impact of this tragic and overwhelming pandemic.
 
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