Nucleoside Analogs and Nucleoside Precursors as Drugs in the Fight against SARS-CoV-2 and Other Coronaviruses

Abstract

Coronaviruses (CoVs) are positive-sense RNA enveloped viruses, members of the family Coronaviridae, that cause infections in a broad range of mammals including humans. Several CoV species lead to mild upper respiratory infections typically associated with common colds. However, three human CoV (HCoV) species: Severe Acute Respiratory Syndrome (SARS)-CoV-1, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2, are responsible for severe respiratory diseases at the origin of two recent epidemics (SARS and MERS), and of the current COronaVIrus Disease 19 (COVID-19), respectively. The easily transmissible SARS-CoV-2, emerging at the end of 2019 in China, spread rapidly worldwide, leading the World Health Organization (WHO) to declare COVID-19 a pandemic. While the world waits for mass vaccination, there is an urgent need for effective drugs as short-term weapons to combat the SARS-CoV-2 infection. In this context, the drug repurposing approach is a strategy able to guarantee positive results rapidly. In this regard, it is well known that several nucleoside-mimicking analogs and nucleoside precursors may inhibit the growth of viruses providing effective therapies for several viral diseases, including HCoV infections. Therefore, this review will focus on synthetic nucleosides and nucleoside precursors active against different HCoV species, paying great attention to SARS-CoV-2. This work covers progress made in anti-CoV therapy with nucleoside derivatives and provides insight into their main mechanisms of action.

Keywords: MERS-CoV; SARS-CoV-1; SARS-CoV-2; coronavirus; favipiravir; molnupiravir; nucleoside drugs; remdesivir; ribavirin; sofosbuvir.

Figure 1

Structures of the nucleoside precursors and derivatives of purine analogs (with drug names and related IUPAC nomenclature) used or under investigation in the HCoV disease therapy.

Figure 2

Mechanism of action of favipiravir.

Figure 3

Structures of the nucleoside analogs (provided with drug names and related IUPAC nomenclature) used or under investigation in the HCoV disease therapy.

Figure 4

Structural representation of remdesivir (with use and IUPAC names, left) and view of its triphosphate form bound to SARS-CoV-2 RdRp in the active site (PDB ID: 7BV2 [132], image obtained using Mol* [133], https://www.rcsb.org/3d-view/7BV2 (accessed on 10 December 2020), right).

Figure 5

Mechanism of the RdRp inhibitory activity of remdesivir and its non-phosphorylated nucleoside form GS-441524.