The objective of our project is to identify antivirals that inhibit SARS-CoV-2 replication by acting on the virus RNA. This addresses an unmet need in the COVID-19 pandemia, since presently there is no effective treatment for the infection caused by the virus.
The research project is based on:
(i) the evaluation and characterization of a variety of RNA-targeted antiviral leads including proprietary protein alpha-helix mimics and drug-like molecules as well as FDA-approved drugs susceptible to repurposing
(ii) the discovery of new leads acting on a highly conserved SARS-CoV-2 RNA functional motif.
Relative to other anti-SARS-CoV agents under investigation, RNA-targeted compounds may have the advantage of reduced rates of resistance because functional RNA structures are frequently conserved. This also means that RNA-directed molecules could be used as wide-spectrum antivirals for treating other virus outbreaks likely to happen in the future.
We have discovered several classes of novel antiretroviral compounds with a mechanism of action based on inhibition of HIV-1 RNA biogenesis processes that will be evaluated against SARS-CoV-2.
The first of these comprises terphenylene compounds that mimic the arginine-rich alpha-helix of the virus-encoded protein Rev, bind to a viral RNA structure called RRE, and inhibit the complex formed between RRE and Rev.
Additional inhibitors of HIV-1 RNA biogenesis have been identified through RRE-Rev-based screens, including FDA-approved drugs susceptible to repurposing as well as drug-like molecules. In addition, we have identified several SARS-CoV-2 RNA motifs potentially suitable for drug discovery.
With the support of CaixaImpulse, we will be able to progress towards two goals:
(i) Identification of new anti-SARS-CoV-2 agents with appropriate toxicity, pharmacokinetic and antiviral properties in vivo, suitable for preclinical research. This will be accomplished by evaluating our library of RNA-targeted antivirals and by applying a chemical optimization process to the most promising hits.
(ii) Discovery of new antiviral leads binding to a highly conserved SARS-CoV-2 RNA structure. For this, we will utilize a high-throughput screening strategy in vitro, and will evaluate the best hits with cellular assays.