7.13 - Ribonucleic Acid Viruses: Antivirals for Influenza A and B, Hepatitis C Virus, and Respiratory Syncytial Virus
This chapter reviews the medicinal chemistry of the current treatment options as well as the experimental drug candidates in the research pipelines for the three most common RNA viruses: influenza, hepatitis C virus (HCV), and respiratory syncytial virus (RSV). The viral replication cycles and the most important aspects of transmission and epidemiology are described to give a basis for the understanding of the medicinal chemistry efforts directed at these viral diseases.
Although all three viruses are RNA viruses, the associated epidemiology, pathology, and treatment options as well as the unmet medical need apparent for these infectious diseases are quite different.
Both influenza and RSV cause largely self-limiting infections. However, both viruses are associated with significant morbidity and mortality in high-risk patient populations. Whereas vaccines have been development successfully against influenza A and B, safe vaccines for RSV are still not available.
RSV poses a particular threat to prematurely born infants and current, prophylactic treatment involves temporary immunization with immunoglobulin antibodies. Here, we review recent progress in the discovery and development of RSV fusion inhibitors, of which the most recent class of benzimidazolones also shows promising oral bioavailability.
Despite the tremendous impact that can be attributed to influenza vaccination, it is still important to have actual treatment options available. The most compelling reason for the latter is the unique ability of influenza A viruses to exchange part of their segmented genome in cells coinfected with several viruses, thereby allowing for sudden, major genetic shifts that cannot be anticipated for vaccine generation. Here, we describe the discovery and development of the most prominent class of influenza antivirals, the neuraminidase inhibitors. Other anti-influenza strategies discussed here include small-molecule targeting of the hemagluttinin-mediated fusion process and the influenza endonuclease-mediated RNA capping process.
HCV is a major cause for chronic infection of the liver, often leading to liver cirrhosis and liver failure. Current therapy, a combination of ribavirin and interferon-α, is leaving approximately half of the patients without a sustained virological response, indicated by the full clearance of the virus. Here, we describe several classes of small molecules targeting the two major viral proteins, the HCV protease (NS3) and the HCV polymerase (NS5b). For the HCV protease, we focus on the discovery of the two most advanced classes of inhibitors, the macrocyclic noncovalent protease inhibitors and the peptidic covalent inhibitors. In case of the HCV polymerase, two approaches have produced potent inhibitors. Several promising nucleosides have been identified that upon incorporation in the growing RNA chain cause chain termination, i.e., the 2'-methyl-ribonucleosides. Furthermore we describe several classes of nonnucleoside inhibitors that act by an allosteric mechanism.