Effective Antiviral Treatment of Systemic Orthopoxvirus Disease: ST-246 Treatment of Prairie Dogs Infected with Monkeypox Virus

New effective chemically synthesized anti-smallpox compound NIOCH-14

“…Another form of the virus (mature intracellular) located in infected target cells can also infect neighbouring cells (although to a limited extent) (McIntosh & Smith, 1996;Stern et al, 1997;Zhang et al, 2000), which, most likely, provided the formation of a relatively high level of antigenic viral load in these animals resulting in substantially increased humoral immunity approaching that of the control group of surviving marmots and after intranasal infection with MPXV. Similar results showing the accumulation of high titres of anti-orthopoxvirus antibodies in experiments involving ST-246 in different animals were also obtained by other researchers (Huggins et al, 2009;Stabenow et al, 2010;Smith et al, 2011).…”

“…This dose range was chosen based on literature data demonstrating that ST-246 at doses from 30 to 100 mg g 21 was effective against many orthopoxvirus infections in experiments on animals other than primates (Nalca et al, 2008;Quenelle & Kern, 2010;Smith et al, 2011).…”

Treatment with the Smallpox Antiviral Tecovirimat (ST-246) Alone or in Combination with ACAM2000 Vaccination Is Effective as a Postsymptomatic Therapy for Monkeypox Virus Infection

“…Tecovirimat targets the product of the vaccinia virus F13L gene (which is highly conserved among other orthopoxviruses) and prevents virus egress from infected cells by reducing the intracellular production and release of enveloped virus (4,5). In numerous animal models (6)(7)(8)(9)(10), tecovirimat has been shown to be highly effective at reducing morbidity and preventing mortality even when treatment is initiated after onset of clinical signs of orthopoxvirus-induced disease. To date, treatment with tecovirimat has not been directly compared to smallpox vaccination to evaluate the relative efficacy of each, nor has there been any investigation into the potential for tecovirimat to negate the efficacy of vaccination (or vice versa) upon combined administration postexposure (as current policy dictates that vaccine-contraindicated individuals would still be vaccinated in the case of a smallpox emergency [11]).…”

Pharmacokinetic and Pharmacodynamic Modeling To Determine the Dose of ST-246 To Protect against Smallpox in Humans

“…Orthopoxvirus strains used in the in vivo studies included vaccinia virus, cowpox virus, ectromelia virus, rabbitpox virus, and monkeypox virus (MPXV) (6-9), (5,10). ST-246 increased survival in all of these studies in a dose-dependent manner (5)(6)(7)(8)(9)(10). Although experimental infection of cynomolgus monkeys via intravenous injection of variola virus can induce disease symptoms that resemble human smallpox, the model does not provide consistent lethality, making the only existing variola animal model inadequate for definitive assessment of the efficacy of a smallpox treatment (11)(12)(13).…”

“…ST-246 is a small-molecule therapeutic that has shown efficacy in multiple in vivo studies of orthopoxvirus infection in mice, rabbits, ground squirrels, prairie dogs, and nonhuman primates (NHPs) (5)(6)(7)(8)(9). Orthopoxvirus strains used in the in vivo studies included vaccinia virus, cowpox virus, ectromelia virus, rabbitpox virus, and monkeypox virus (MPXV) (6-9), (5,10).…”