• The most famous member of the genus is Variola virus, which causes smallpox. The initial symptoms include fever, malaise, head and body aches, and sometimes vomiting. Lesions that developed into crater-like ulcers surrounded by inflammatory tissue and eventually covered by thick black crusts are the characteristic indicators of Orthopox infection. Severe edema and erythema may affect large areas in cases of severe infection. It was wiped out using Vaccinia virus, as a vaccine in 1977. Routine civilian vaccination was discontinued, leaving the majority of the world’s population unprotected against smallpox. Recently, strategies for prevention and treatment of Orthopox infection have received attention due to concerns that poxviruses, which can result in death for over 30% of cases among unvaccinated individuals, could be utilized for bioterrorism.
• As is the case for most viruses, the capsid assembly pathway of orthopox viruses has not been characterized and, therefore, might be an excellent target for antiviral therapeutics. The Prosetta antiviral platform identifies compounds that interfere with this pathway through interactions with host proteins critical for catalysis of capsid assembly. Prosetta has identified a handful of small molecule pre-lead hits which demonstrate anti-orthopox activity in a live virus cell culture assay, with several EC50’s below 1 uM. One promising compound demonstated excellent potency (EC50 < 100 nM) in the live virus cell culture assay and low cytotoxicity (CC50 > 25 mM, Vero cells), resulting in a selectivity index of greater than 250.