Nucleosides for the treatment of respiratory RNA virus infections

Abstract

Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild seasonal colds. These RNA viruses can also cause lower respiratory tract infections leading to bronchiolitis and pneumonia. Young children, the elderly, and patients with compromised cardiac, pulmonary, or immune systems are at greatest risk for serious disease associated with these RNA virus respiratory infections. In addition, swine and avian influenza viruses, together with severe acute respiratory syndrome-associated and Middle Eastern respiratory syndrome coronaviruses, represent significant pandemic threats to the general population. In this review, we describe the current medical need resulting from respiratory infections caused by RNA viruses, which justifies drug discovery efforts to identify new therapeutic agents. The RNA polymerase of respiratory viruses represents an attractive target for nucleoside and nucleotide analogs acting as inhibitors of RNA chain synthesis. Here, we present the molecular, biochemical, and structural fundamentals of the polymerase of the four major families of RNA respiratory viruses: Orthomyxoviridae, Pneumoviridae/Paramyxoviridae, Coronaviridae, and Picornaviridae. We summarize past and current efforts to develop nucleoside and nucleotide analogs as antiviral agents against respiratory virus infections. This includes molecules with very broad antiviral spectrum such as ribavirin and T-705 (favipiravir), and others targeting more specifically one or a few virus families. Recent advances in our understanding of the structure(s) and function(s) of respiratory virus polymerases will likely support the discovery and development of novel nucleoside analogs.

Keywords: RNA-dependent RNA polymerase; Respiratory syncytial virus; antiviral; coronavirus; influenza; nucleoside analog; picornavirus; rhinovirus.

Figure 1.

Prevalence of respiratory viruses in a PICU. Prevalence was defined as number of cases per 1000 admissions with respiratory distress.⁴ PICU: pediatric intensive care unit.

Figure 2.

(a) The ribbon model of the influenza A polymerase complex, which is composed of three subunits that assemble a 270 kDa trimer. The trimer consists of the (PA) protein (blue), PB1 (teal), and PB2 (green). (b) Within the PB1 domain is the RdRp, which adopts a right-handed arrangement with the fingers (blue), palm (red), thumb, (yellow), and a priming loop (purple).⁴⁶ PA: polymerase acidic; PB1: polymerase basic protein 1; PB2: polymerase basic protein 2; RdRp: RNA-dependent RNA polymerase.

Figure 3.

(a) A homology-model of the RdRp domain of the RSV L protein shows a right-handed fold with structural similarities to VSV (b) when the two structures are overlayed (RSV RdRp is shown in blue, VSV RdRp is shown in red).^68,71 (c) The three-dimensional structure of the methyltransferase (green) and C-terminal (blue) domains of the HMPV L protein.⁷² RdRp: RNA-dependent RNA polymerase; RSV: respiratory syncytial virus; VSV: vesicular stomatitis virus; HMPV: human metapneumovirus.

Figure 4.

(a) The HRV16 3D^pol in a ribbon representation showing the classic right-handed model with the fingers (blue), palm (red), and thumb (yellow) subdomains.⁸⁶ (b) The palm subdomain showing motifs A–E. HRV: human rhinovirus.

Figure 5.

The chemical structures of a range of antiviral compounds. These structures describe the broad-spectrum ribavirin approved for HCV and severe RSV, the inhibitors NITD008 and 7DMA for rhinoviruses, the influenza virus inhibitors 2′FdG and T-705, ALS-8176 for RSV virus infection, and GS-5734, an Ebola virus inhibitor. HCV: hepatitis C virus; RSV: respiratory syncytial virus; 7DMA: 7-deaza-2′-C-methyladenosine; 2′FdG: 2′-deoxy-2′-fluoro guanosine.