Orthopoxvirus Targets for the Development of Antiviral Therapies

Abstract

The potential use of smallpox virus as a bioterror agent and the endemic presence of monkeypox virus in Africa underscores the need for better therapies for orthopoxvirus infections. The only existing clinical experience treating vaccinia and smallpox infections has been with Marboran, which suggested that antiviral therapies could be effective in treating and preventing smallpox infections, but this compound has not been pursued. Drugs that have been approved for other indications, like cidofovir, could be approved for the treatment of orthopoxvirus infections in a timely manner, and this compound has already been approved for emergency treatment of smallpox and complications from vaccination. Its lack of activity when given orally, however, limits its use in a major outbreak involving large numbers of people exposed to the virus. The discovery and development of new therapies can be achieved more rapidly by drawing on the experience and successes with other antiviral agents, particularly with the herpesviruses. This review will discuss the orthopoxvirus replication cycle in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug design and development. This discussion is designed to help investigators relate these targets to parallel functions and existing assays in other virus systems that have been used successfully in drug development. The rapid progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new strategies for antiviral therapy with other viruses.

Mechanism of Antiviral Drug Resistance of Vaccinia Virus: Identification of Residues in the Viral DNA Polymerase Conferring Differential Resistance to Antipoxvirus Drugs

“…Consequently, antiviral drugs appear to be essential for the treatment of severe poxviral disease. The development of new antipoxvirus agents not only would provide health authorities with a means of containing smallpox but could also be used to treat MCV infections as well as the rarer infections caused by monkeypox virus, cowpox virus, and Orf virus (6,41,45). Such drugs could also prove very useful for treating adverse responses to vaccines, and indeed, the usefulness of antiviral agents in the treatment of severe eczema vaccinatum in a household contact of a smallpox vaccinee was recently reported (54).…”

Smallpox: Virology, Clinical Presentation, and Prevention

“…Ribavirin has been shown to inhibit variola major in vitro [83]. More recently, cidofovir has been shown to have activity against smallpox virus both in vitro and in vivo [83][84][85][86][87][88]. An oral analogue is being developed [84,89,90].…”

Identification of a Pyridopyrimidinone Inhibitor of Orthopoxviruses from a Diversity-Oriented Synthesis Library

“…Numerous small-molecule inhibitors of orthopoxviruses have been identified; however, many are nucleoside analogs for which selectivity for viral over host enzymes poses developmental challenges (5,22). Compounds that show promise in preclinical or clinical settings are the cidofovir derivative CMX001 (24), which is a nucleoside analog, and ST-246 (12,13), which has a unique mechanism of action in preventing viral egress from infected cells.…”