Discovery of RNA-binding antivirals for treatment of COVID-19

Summary

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.

Achievements

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.

Next Steps

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.

Team

Research Professor

José Gallego

Project leader

Assistant Professor

Kris White

Associate Professor

Vicente Marchán

PhD student

Álvaro Simba

COVID-19

Scientific Area

Pharmacology

Business area

Therapeutic

Research center

Universidad Católica de Valencia