A Novel Therapeutic Approach to Polyomavirus-Associated Diseases

Polyomaviruses infect most individuals soon after birth and usually form latent, nonhazardous infections. In immunosuppressed populations, however, polyomavirus reactivation can lead to disease. For example, reactivation of BK virus in renal transplant patients results in BKvirus associated nephropathy. In addition, ~2.5 million AIDS patients are currently afflicted with Progressive Multifocal Leukoencephalopathy, a myelin degenerative disease caused by reactivation of JC virus. Current treatments for these diseases (e.g., Cidofovir) non-specifically target DNA replication, which cause many undesirable side effects. Therefore, developing a specific anti-polyomaviral therapeutic is an essential undertaking. All polyomaviruses express Large Tumor Antigen (TAg), a protein that is produced early after infection, has no human homologue, and is required for viral replication. TAg is a AAAATPase and also harbors an N-terminal J domain, which binds host cell-encoded Hsp70. The AAA-ATPase activity is required to support viral DNA replication, whereas the J domain-Hsp70 interaction is required to drive the host cell into S phase. To identify new anti-polyomavirus therapeutics, we tested several derivatives of a previously identified anti-TAg chemical scaffold to identify compounds with enhanced anti-viral activity. Preliminary in vitro data indicate that an optimized compound (SMAL) generated from these structure-activity relationships shows particular promise as an anti-viral agent due to its ability to potently inhibit TAg AAA-ATPase activity. The compound also modestly inhibits host Hsp70. We hypothesize that the two-pronged action of this small molecule will translate into improved anti-viral properties. To this end, cellbased viral replication assays with SMAL and its precursor compounds are being conducted to test our hypothesis. Future studies will aim to design, synthesize, and test subsequent SMAL derivatives that may hold even greater therapeutic potential against polyomavirus-associated diseases.