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Arndt W, Mitnik C, Denzler KL, White S, Waters R, Jacobs BL, et al. (2012) In Vitro Characterization of a Nineteenth-Century Therapy for Smallpox. PLoS ONE 7(3): e32610. https://doi.org/10.1371/journal.pone.0032610
Introduction
In the late 1800's, the Micmac Indians of Nova Scotia proclaimed the existence of a botanical-based remedy for smallpox. During this time, Herbert Miles, the Assistant Surgeon to the Royal Artillery, reported that during an outbreak of smallpox “an old squaw going amongst them, and treating the cases with (a botanical) infusion…was so successful as to cure every case”. This botanical infusion was later described as being derived from the carnivorous plant, Sarracenia purpurea [1], [2].
In 1892, Charles Millspaugh described that the Native Americans of eastern North America used S. purpurea as a poultice against smallpox and it provided “the greatest remedy known for the dreadful scourge” [3]. C.G. Logie, Surgeon-Major of the Royal Horse Guards, treated variola-infected men in his regiment and found that S. purpurea “seemed to arrest the development of the pustules, killing, as it were, the virus from within, thereby changing the character of the disease and doing away with the cause of pitting” [4]. However, the putative medicinal properties of S. purpurea have been largely forgotten.
Before human development, S. purpurea, also known as Huntsman's Cup, Side-saddle flower or Indian Pitcher Plant, was widely distributed ranging from Labrador to Florida along the Atlantic seacoast of North America and westward to Wisconsin and Minnesota [13], [14]. S. purpurea is an insectivorous bog plant, the leaves of which form cups and become filled with water to capture insects.
Smallpox outbreaks have occurred within the human population for thousands of years, but the natural disease is now considered eradicated after a successful worldwide vaccination program. In recent years there has been a heightened concern that variola virus might be used as an agent of bioterrorism [30]. In addition, the related monkeypox virus represents an emerging threat to the human population [19], [30]. Though the vaccine provides effective protection against poxvirus infection, side effects and risks associated with the smallpox vaccine are reasonably common and can be quite severe [27], [30]. The increasing threat of Orthopoxvirus-related infections highlights the need to discover effective poxvirus countermeasures. In this manuscript we present the ‘rediscovery’ and characterization of S. purpurea as an effective inhibitor of Orthopoxvirus replication.
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Our data supports that extracts of S. purpurea effectively inhibit the replication of VACV, MPXV and VARV in vitro. This activity toward Orthopoxviruses is consistent with the historical reports of S. purpurea as a therapy against smallpox infections. The goal of this study was to characterize anti-poxvirus activity of S. purpurea extracts in order to verify and evaluate the botanical material under similar preparation methods as that done historically in the 1800's. Collectively, the data suggests that S. purpurea targets early viral transcription leading to an inhibition in viral replication. In comparison to other botanicals, the data demonstrate that the anti-poxvirus activity of the S. purpurea extract was not necessarily shared by other botanicals. Based on the results presented, future work will involve fractionation and identification of the active anti-poxvirus constituent(s) present in the S. purpurea extracts. Cidofovir (CDV) is a broad spectrum antiviral with activity against several DNA viruses, including poxviruses. Currently, CDV is the only licensed parenteral drug with antipoxvirus activity, but its clinical use is governed by its Investigational New Drug (IND) status [30]. Since CDV leads to nephrotoxicity and must be administered intravenously, CDV has not been sought as the standardized therapy to treat poxvirus infections [20]. CMX001, synthesized by coupling CDV to hexadecyl propanedial alkoxykanol, is currently being investigated as an alternative to CDV due to increased bioavailability after oral administration and predicted lack of nephrotoxicity [31]. Another compound, ST-246 (Tecovirimat), has been shown to be highly efficacious in the treatment of poxviruses. ST-246 can be delivered orally and has been reported to be nontoxic within an animal model [21], [32]. To date, ST-246 and CMX001 are the most promising antipoxvirus compounds. A report issued by the Institute of Medicine, as well as the 2009 WHO Advisory Committee on Variola Virus Research, suggested that due to the increased susceptibility of the human population to smallpox, at least two anti-variola virus drugs with different mechanisms of action should be developed in order to provide greater protection in the event of a smallpox epidemic [22]. ST-246 and CMX001 have potent efficiencies and target different points in the viral replication cycle, but single point mutations in the poxvirus genome can confer resistance to these drugs. Therefore, additional anti-poxvirus therapies would certainly aid in protecting the human population and increase the repertoire of treatments available...