Efficacy of Delayed Treatment with ST-246 Given Orally against Systemic Orthopoxvirus Infections in Mice

Abstract

ST-246 was evaluated for activity against cowpox virus (CV), vaccinia virus (VV), and ectromelia virus (ECTV) and had an in vitro 50% effective concentration (EC 50 ) of 0.48 M against CV, 0.05 M against VV, and 0.07 M against ECTV. The selectivity indices were >208 and >2,000 for CV and VV, respectively. The in vitro antiviral activity of ST-246 was significantly greater than that of cidofovir, which had an EC 50 of 41.1 M against CV and 29.2 M against VV, with selectivity indices of >7 and >10, respectively. ST-246 administered once daily by oral gavage to mice infected intranasally with CV beginning 4 h or delayed until 72 h postinoculation was highly effective when given for a 14-day duration using 100, 30, or 10 mg/kg of body weight. When 100 mg/kg of ST-246 was administered to VV-infected mice, a duration of 5 days was sufficient to significantly reduce mortality even when treatment was delayed 24 h postinoculation. Viral replication in liver, spleen, and kidney, but not lung, of CV-or VV-infected mice was reduced by ST-246 compared to levels for vehicle-treated mice. When 100 mg/kg of ST-246 was given once daily to mice infected by the intranasal route with ECTV, treatment for 10 days prevented mortality even when treatment was delayed up to 72 h after viral inoculation. Viral replication in target organs of ECTV-infected mice was also reduced.National preparedness for bioterrorist events includes the development of rapid detection techniques, improved vaccination strategies, and antimicrobial chemotherapeutics with differing modes of action or targets. Preparing for a weaponized variola virus release is one component necessary for national security, and the development of highly effective, nontoxic antiviral agents that have proven efficacy when given postexposure is essential. Although cidofovir (CDV) has been approved under investigational new drug application for treatment of smallpox or complications of vaccination, its use would be limited since it is not orally bioavailable and produces nephrotoxicity.Previous evaluation of ST-246 for activity against orthopoxviruses has shown both in vitro and in vivo efficacies (13). When evaluated in vitro against vaccinia virus (VV), cowpox virus (CV), ectromelia virus (ECTV), monkeypox virus, camelpox virus, and variola virus, ST-246 inhibited virus replication by 50% at a concentration (50% effective concentration [EC 50 ]) of Յ0.07 M. In animal models using lethal infections with ECTV or VV, ST-246 was reported to be nontoxic and effective against mortality when given orally twice daily at 50 mg/kg of body weight for 14 days beginning before or shortly after infection. ST-246 was also evaluated in the nonlethal mouse tail lesion model by use of intravenous VV to mimic the primary viremic phase of viral infection and systemic lesional disease. When ST-246 was administered by oral gavage at 15 or 50 mg/kg twice daily for 5 days, the tail lesions were significantly reduced (13).The current studies expand upon the previous in vitro and in vivo findings and furt...

A Mouse Model of Lethal Infection for Evaluating Prophylactics and Therapeutics against Monkeypox Virus

“…In the ECTV/mousepox model, we and others have evaluated successful, delayed dosings with CMX001 and ST-246 (39,40). Further evaluation of dosing regimens would be a logical next step in evaluating drug efficacy against MPXV in C57BL/6 stat1 Ϫ/Ϫ mice.…”

Orthopoxviruses Require a Functional Ubiquitin-Proteasome System for Productive Replication

“…Currently used poxviral therapeutics include cidofovir, a nucleotide analogue that successfully inhibits orthopoxvirus infections both in vivo and in vitro (7,38). Additionally, screening approaches have yielded other compounds that inhibit orthopoxvirus infection, including ST-246, which prevents successful virus formation and is effective in animal models (8,47), and mitoxantrone, an anticancer agent that inhibits a late-stage assembly step of vaccinia virus (15). Our data indicate that the treatment of orthopoxvirus-infected cells with proteasome inhibitors or an E1 inhibitor dramatically affects late gene expression, suggesting that proteasome inhibitors or E1 inhibitors could potentially be employed as antivirals.…”

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

“…The effective concentration of compound required to inhibit virus-induced cytopathic effect by 50% is less than 0.07 M and 0.04 M against six VARV strains and five MPXV strains, respectively (25). The potent, prophylactic or postexposure protective antiviral activity of ST-246 in vivo has been described by numerous investigators using multiple animal models of virulent OPXV illness (1,8,10,19,20,24,27). Although these studies document ST-246 as an effective antiviral drug for prophylactic or postexposure treatment of OPXV infections, they do not address potential human therapeutic use of ST-246, i.e., after definitive rash illness onset.…”