Review A survey of antiviral drugs for bioweapons

Smallpox (variola major), and the haemorrhagic fever viruses (filoviruses and arenaviruses) are classified as Category A biowarfare agents by the Centers for Disease Control. Category A agents pose a significant risk to public health and national security because they can be easily disseminated by aerosol, although with the excep- tion of variola, they are not easily transmitted from person to person. An attack with these viruses would result in high morbidity and mortality and cause widespread panic. With the exception of smallpox and Argentine haemor- rhagic fever virus, there are no vaccines or approved treatments to protect against these diseases. In this review we focus on promising prophylactic, therapeutic and disease modulating drugs (see Figure 1 for select chemical structures). ©2005 International Medical Press 0956-3202 Bioweapons are a threat to global health. Unlike nuclear and chemical weapons, virus-based biological weapons (BW) are part of the natural global flora and fauna, with one notable exception, smallpox. In this review we will focus on inhibitors of arenaviruses, poxviruses, and filoviruses. In general there are three types of inhibitors needed for effective biodefence: i) Prophylactic treatments which enable the individual to resist infection and would help limit the spread of a BW agent. Drugs of this type are scarce and of the class A viruses, only members of the Orthopoxvirus genus have promising prophylactic drug candidates. ii) Therapeutic treatments that inhibit viral replication, reduce viral load and consequently limit the degree of mortality and morbidity. iii) Disease modifiers that do not act directly against the virus but rather target aspects of the viral pathogenesis and act to transform the host into an inhospitable environment for viral replication. These different classes of compounds can either be specific to the virus or broad-acting. Broad-acting compounds are attractive because there would be fewer compounds to stockpile as contingencies. In all cases, compounds need to be orally available to facilitate the rapid distribution and dosing of huge numbers of people in case of a large-scale attack. Infection with BW agents can be significantly different than an infection with their counterparts in nature. These agents may be delivered in ways that the natural virus is not usually transmitted and possibly at infectious doses that are many times what occurs in nature. These nonstandard routes may produce diseases that are distinct from natural forms of the disease. To further complicate the problem, these viruses could be genetically engineered to overcome vaccines, therapeutics and detection. The combination of these alternatives with a few viruses significantly amplifies the issues surrounding drug discovery for BW agents. Understanding what types of compounds are effective at inhibiting viral replication will aid in developing drugs that address possible genetic modifications. An effective antiviral serves another important role aside from limiting replication during an infection. In its stockpiled form, it may discourage use of a particular BW agent. Furthermore, because some of these viruses are endemic in different parts of the world, the ability to effectively treat the infec- tions they cause will be a significant boon to global public health.