We are proposing a study to further develop two compound classes as potential antipoxvirus agents. The leads for our study are carbocyclic 3-deazaadenosine, which has reproducible and potent in vitro and in vivo anti-vaccinia virus activities, and N1- aralkyloxyadenosines, which have reproducible and potent in vitro anti- vaccinia virus activity, but have not yet been examined in vivo. The in vitro activities for both lead compounds groups were previously discovered in a USAMRIID compound screen against viruses of interest to the Army, while the in vivo anti-vaccinia activity has been recently seen in a USAMRIID study of compounds as potential antipoxvirus agents. Our efforts toward the proposed carbocyclic 3-deazaadenosine analogues will be directed toward optimizing both their antipoxvirus activities as well as their S-adenosylhomocysteine (SAH) hydrolase inhibition. A close relationship has been noted between these two properties in our lead compound and in a number of other nucleoside analogues reported in the literature. We will be targeting new carbocyclic 3-deazaadenosine analogues and other nucleoside analogues that have a modified 5-prime side chain that can interact with the hydrophobic and hydrophilic groups in the hydrolase pocket that normally interact with the homocysteine of S-adenosylhomocysteine. Our pursuit of new analogues of our N1-aralkyloxyadenosines lacks a mechanistic rationale, and thus, we will be preparing new analogues with aralkyl (both heterocyclic and benzylic) and cycloalkyl groups that can help in both the optimization of their anti-vaccinia activities and the elucidation of the mechanism of action will be joint focuses. The synthesis of all of our target compounds will be pursued in SRI. Larger quantities of any promising leads can also be synthesized in our Prep laboratories. The design of future targets will be a joint effort between SRI and our group of collaborators. Dr. John Huggins of USAMRIID, Dr. Ronald T. Borchardt of the University of Kansas, and Dr. Erik De Clercq of the Rega Institute in Belgium will be evaluating our compounds for their antipoxvirus activities and their SAH hydrolase inhibition. Dr. Stewart Shuman of the Sloan Kettering Research Institute will be helping us by concentrating on the mechanism of action of the N1-aralkyloxyadenosine analogs.
