Anti-Orthopoxvirus Drug Discovery and Development
Stewart W. Schneller
Professor of Chemistry and
Dean, College of Sciences and Mathematics
Auburn University
Auburn, Alabama 36849-5319
schnest@auburn.edu



picture of research group
The Schneller research group:
Standing on ground, left to right: Wei Ye, Atanu Roy
Standing on ledge, left to right: Dean Schneller, Elaine Bailey, Tanya Shulyak, Jian Zhou
Sitting on top, left to right: Akin Akdag, Cliff Yin, Minmin Yang, Tesfaye Serbessa


Background
 Within the Poxviridae family of viruses is the genus Orthopoxvirus, which includes variola, cowpox, vaccinia, and monkeypox viruses. Variola is the etiological agent of smallpox, which is a contagion that has confronted humankind for centuries with debilitation, morbidity and death [1]. However, through an intensive 50-year international vaccination effort, the last known natural case of smallpox was diagnosed in 1977. In 1980, the disease was declared eradicated by the World Health Organization and immunization ceased [2]. Because of the highly infectious and deadly properties of smallpox, little authorized research has taken place on it. The only legal repositories of the smallpox virus are in the United States and in Russia: Centers for Disease Control (Atlanta) and State Research Center for Virology and Biotechnology (Novosibirsk, Siberia).

In light of the waning immunity to smallpox infection and because of the possibility that it could reappear, the World Health Organization has called for a delay in the destruction of the two aforementioned known sources of variola virus. This decision was based on a compelling need for long term retention of live variola virus for the development of antirviral agents or novel vaccines to protect against a re-emergence of smallpox [3]. In supporting this decision, Secretary of the U.S. Department of Health and Human Services, Donna Shalala, said [3] "currently there is no effective antiviral agent that could be used to treat infected individuals or to prevent variola, and the current vaccine is in short supply and cannot be used in immunocompromised individuals." The limited supply of vaccine is also of questionable purity due to rubber seal contamination and uncertain shelf-life stability [4]. Thus, the development of new antiviral agents and vaccine candidates to confront re-emergence of smallpox is urgent. It is the search for new drugs for this purpose that is the focus of this research.

Basis for Drug Design
 The poxvirus family is considered [5] to be more advanced among the DNA viruses because their DNA replication and mRNA formation occurs in the cytoplasm and because they encode a sizeable number of enzymes and proteins specific to their own development (rather than depending more exclusively on those of host cellular origin). This latter unique characteristic forms the basis for selective drug design to affect orthopoxvirus replication (specifically, variola) in the Schneller laboratory.

Examples of virally encoded enzymes, which amend themselves to rational drug development for this purpose are: DNA polymerase, RNA polymerase, mRNA guanine-7-methyltransferase, mRNA 2'-O-nucleoside methyltransferase, mRNA capping enzyme complex, early transcription factor, poly(A)polymerase, nucleoside triphosphate phosphohydrolase I and II, nicking-joining enzyme, DNA topoisomerase, and protein kinase. Many of these enzymes have been isolated from vaccinia [5], an orthopoxvirus that has served as a laboratory model for smallpox and was the source of the extensive smallpox vaccination program. Additionally, to facilitate the high levels of DNA synthesis that occur upon infection, poxviruses encode for thymidine kinase and ribonucleotide reductase [6].



Research Plan
 In recent years, the Schneller group has devoted attention to seeking new antiviral agents [7] whose mode of action is the inhibition of viral specific methyltransferases, such as the aforementioned mRNA guanine-7-methyltransferase and mRNA 2'-O-nucleoside methyltransferase. Such methylation reactions are required for final processing of the 5'-capped structure of mRNA (as m7Gppp6AmpApm…) from cellular and viral (including orthopox) sources [8]. Therefore, inhibitors of viral methyltransferases can be expected to prevent maturation of mRNAs and, in turn, limit the production of the requisite proteins and enzymes for generation of progeny viral particles [8b]. In fact, it has been shown [9] that vaccinia guanine-7-methyltransferase and 2'-O-nucleoside methyltransferase are likely to be vulnerable to synthetic inhibitors.

The methyltransferase inhibitors under consideration in the Schneller laboratory as a source of new drugs effective against variola are based on carbocyclic nucleosides. In such molecules, the ribofuranose moiety of traditional nucleosides is replaced by a cyclopentane ring (for example, 1, aristeromycin, which is naturally occurring carbocyclic adenosine) [10]. This structural alteration renders the analogs resistant to phosphorylases, which cleave the glycosidic bond of standard nucleosides, and, consequently, improves their stability as potential medicinal agents [10a]. Also, conformational changes and stereoelectronic perturbations that occur with replacing the ribofuanose unit with a cyclopentyl ring bring about the unique biological properties of carbocyclic nucleosides [10e]. In addition to their antiviral properties, carbocyclic nucleosides have been shown to be anti-tumor [11], anti-leishmanial [12], and anti-trypanosomal [13] candidates and to serve as probes for enlightening biochemical processes [14].

The results from the Schneller research are expected to not only find usefulness in treating smallpox infections but to also play a role in confronting new emerging infectious diseases heretofore thought to be inconsequential to humans [15].

 

 

Literature Cited