SARS-CoV-2 RNA-dependent RNA polymerase as a therapeutic target for COVID-19

ABSTRACT

Introduction: The current SARS-CoV-2 pandemic urgently demands for both prevention and treatment strategies. RNA-dependent RNA-polymerase (RdRp), which has no counterpart in human cells, is an excellent target for drug development. Given the time-consuming process of drug development, repurposing drugs approved for other indications or at least successfully tested in terms of safety and tolerability, is an attractive strategy to rapidly provide an effective medication for severe COVID-19 cases.

Areas covered: The currently available data and upcominSg studies on RdRp which can be repurposed to halt SARS-CoV-2 replication, are reviewed.

Expert opinion: Drug repurposing and design of novel compounds are proceeding in parallel to provide a quick response and new specific drugs, respectively. Notably, the proofreading SARS-CoV-2 exonuclease activity could limit the potential for drugs designed as immediate chain terminators and favor the development of compounds acting through delayed termination. While vaccination is awaited to curb the SARS-CoV-2 epidemic, even partially effective drugs from repurposing strategies can be of help to treat severe cases of disease. Considering the high conservation of RdRp among coronaviruses, an improved knowledge of its activity in vitro can provide useful information for drug development or drug repurposing to combat SARS-CoV-2 as well as future pandemics.

KEYWORDS:

• COVID-19
• drug repurposing
• nucleoside inhibitors
• rna polymerase
• sars-CoV-2

Article highlights

• • RNA‐dependent RNA polymerase (RdRp) plays an essential role in SARS‐CoV‐2 viral replication.

• • RdRp motifs are highly conserved among coronaviruses and RNA positive-stranded viruses, offering an attractive target for broad-spectrum antivirals

• • This review focuses on most promising repurposed drugs inhibiting the SARS-COV-2 RdRp

• • For each drug, in vitro and in vivo data against SARS-COV-2 are summarized

• • The review provides an expert opinion of the clinical use of nucleoside analogs in COVID-19 treatment

This box summarizes key points contained in the article.

Declaration of interest

M Zazzi has received grants and personal fees from Gilead Sciences, Janssen-Cilag, Merck Sharp and Dohme, ViiV Healthcare, outside the current work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was partially supported by funds from Ministero dell'Istruzione, dell'Università e della Ricerca, project PRIN 2017, ORIGINALE CHEMIAE in Antiviral Strategy - Origin and Modernization of Multi-Component Chemistry as a Source of Innovative Broad-Spectrum Antiviral Strategy (cod. 2017BMK8JR).