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CHAPTER 4

Discovery and Development of Antiviral Drugs for Treatment of Pathogenic Human Orthopoxvirus Infections

Smallpox, a devastating disease with mortality rates of upwards of 30%, ravaged humanity for thousands of years until it was eradicated in the latter half of the twentieth century by a successful vaccination campaign sponsored by the World Health Organization. Smallpox was caused by infection with variola virus, one of several orthopoxviruses that infect humans and cause disease. Although smallpox no longer exists in the environment, concern that variola virus or a related orthopoxvirus could be developed into a bioweapon prompted the US government to sponsor research into developing antiviral drugs to treat variola virus infection. Antiviral drug development for orthopoxvirus infections is hampered by the lack of human disease, requiring the use of animal models to establish pharmacokinetic–pharmacodynamic relationships to guide effective human dosing strategies. Cidofovir, CMX001 and ST‐246 are clinical‐stage compounds currently being evaluated for the treatment of pathogenic orthopoxvirus infections. Cidofovir is an acyclic nucleoside phosphonate that targets the viral polymerase and CMX001 is an oral prodrug of cidofovir designed to improve oral bioavailability and safety. ST‐246 is a novel chemical entity that blocks viral egress. Although all three compounds are effective at treating orthopoxvirus infections in animal models, and are safe and well tolerated in human clinical trials, establishing effective human dosing strategies using animal efficacy data remains a major challenge for the development of these therapeutics.

Publication details

Print publication date
10 Jun 2013
Copyright year
2013
Print ISBN
978-1-84973-657-2
PDF eISBN
978-1-84973-781-4

From the book series:
Drug Discovery