Synthesis and structure­activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target.

Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirusassociated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side effects. However, all polyomaviruses express Large Tumor Antigen (T Ag), which is unique to this virus family and may serve as a therapeutic target. Previous screening of pyrimidinone­peptoid hybrid compounds identified MAL2-11B and a MAL2-11B tetrazole derivative as inhibitors of viral replication and T Ag ATPase activity (IC50 of ~20-50 µM. To improve upon this scaffold and to develop a structure­activity relationship for this new class of antiviral agents, several iterative series of MAL2-11B derivatives were synthesized. The replacement of a flexible methylene chain linker with a benzyl group or, alternatively, the addition of an ortho-methyl substituent on the biphenyl side chain in MAL2-11B yielded an IC50 of 50 µM, which retained antiviral activity. After combining both structural motifs, a new lead compound was identified that inhibited T Ag ATPase activity with an IC50 of 50 µM. We suggest that the knowledge gained from the structure­activity relationship and a further refinement cycle of the MAL2-11B scaffold will provide a specific, novel therapeutic treatment option for polyomavirus infections and their associated diseases.

Comparative genetic mapping points to different sex chromosomes in sibling species of wild strawberry (Fragaria).

Separate sexes have evolved repeatedly from hermaphroditic ancestors in flowering plants, and thus select taxa can provide unparalleled insight into the evolutionary dynamics of sex chromosomes that are thought to be shared by plants and animals alike. Here we ask whether two octoploid sibling species of wild strawberry--one almost exclusively dioecious (males and females), Fragaria chiloensis, and one subdioecious (males, females, and hermaphrodites), F. virginiana--share the same sex-determining chromosome. We created a genetic map of the sex chromosome and its homeologs in F. chiloensis and assessed macrosynteny between it and published maps of the proto-sex chromosome of F. virginiana and the homeologous autosome of hermaphroditic diploid species. Segregation of male and female function in our F. chiloensis mapping population confirmed that linkage and dominance relations are similar to those in F. virginiana. However, identification of the molecular markers most tightly linked to the sex-determining locus in the two octoploid species shows that, in both, this region maps to homeologues of chromosome 6 in diploid congeners, but is located at opposite ends of their respective chromosomes.