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.