Nucleosides for the treatment of respiratory RNA virus infections

Jordan, Paul C; Stevens, Sarah K; Deval, Jerome

Presently, six HCoV are recognized: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, and the well-known SARS and MERS CoV. 33 These CoV can be further characterized based on genera of Alpha, Beta, Gamma, or Delta; the Alpha and Beta CoV comprise the six viruses mentioned above, and are those that infect humans. CoV 229E and OC43 are both pathogens associated with the common cold, but can cause pneumonia as well. 34 HCoV-NL63 and HCoV-HKU1 infection show similar clinical features to those in patients with 229E and OC43, but clinicians have also reported bronchiolitis, croup, and pneumonia in infected individuals. 35, 36 The first CoV recognized as pandemic threat is SARS-CoV. SARS was discovered in 2002-2003 after a perplexing epidemic of pneumonia among hospital workers in China. 37 By the end of its global epidemic, SARS disseminated to 29 countries, infecting over 8000 individuals, and killing roughly 10% of those infected. 38 Roughly a decade later, a similar pattern occurred with MERS, which began in 2012 in Jordan with an outbreak of a respiratory illness among hospital workers, one of whom died of the infection. Later that year, a man with pneumonia and multiple organ failure in Saudi Arabia was found to have the MERS pathogen. 39 Adults are the target population for both SARS and MERS with a median age range of 39-50 years; MERS occurs predominantly in men whereas SARS does not. The clinical features of both SARS and MERS range from mild to severe respiratory illness, fever, chills, cough, shortness of breath, vomiting, and diarrhea, with the latter displaying a more lethal pneumonia and renal failure. 40, 41 Even worse than SARS mortality, retrospective analysis has shown that of the 2040 confirmed cases of MERS, 35% were fatal. 42 Viral polymerase: An important molecular target for antiviral therapy Nucleoside analogs represent one of the dominant classes of antiviral agents due to their widespread use against the common chronic infections caused by human immunodeficiency virus (HIV), hepatitis B virus, and herpesviruses. In the past 15 years, multiple nucleoside and nucleotide analogs have been developed as direct-acting agents against RNA virus infections such as hepatitis C virus (HCV), but have not yet been successfully applied to acute infections caused by respiratory viruses. Only a handful of nonnucleoside drugs have been developed for the treatment and prevention of these viruses. Such drugs include the FDA approved oseltamivir, zanamivir, and peramivir for influenza virus infection, palivizumab for RSV prevention, as well as the two discontinued clinical candidates targeting rhinovirus, pleconaril and rupintrivir. These molecules possess limitations preventing their widespread use, such as short therapeutic window and risk of resistance selection for the neuraminidase inhibitors, and only partial protection associated with prophylactic use for palivizumab. This has provided the impetus for the approval of new drugs with a broader therapeutic use.