Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.ATPase | diversity oriented synthesis | isosteres | UPCMLD | alpha-methylene cyclopentenone

No abstract

Abstract. The coming century is predicted to feature enhanced climatic variability, including increased frequency, intensity, and duration of extreme climatic events. Ecologists are faced with the critical challenge of anticipating potentially nonlinear ecosystem responses to these changes. High-resolution paleoecological data sets that capture past ecosystem responses to climate variability provide valuable long-term perspectives on the sensitivity of ecosystems to climate-forced state shifts. We used a suite of paleoecological analyses at Titus Bog in northwestern Pennsylvania, USA, to test the hypothesis that the development and expansion of floating peatlands in kettlehole basins represents a threshold response to hydroclimate variability. In contrast with expectations of gradual autogenic peat mat expansion, our results indicate that peat mat expansion at Titus Bog was highly episodic and occurred in three distinct pulses centered on 800, 650, and 400 cal yr BP. Each of these expansion events coincided with or immediately followed decadal-to-mutlidecadal droughts recorded in regional paleoclimate reconstructions. These patterns indicate that peatland development in kettlehole basins can follow nonlinear trajectories, with episodes of rapid advancement triggered by climatic forcing. Future climate changes may increase the likelihood of peatland expansion in kettlehole basins, potentially leading to abrupt changes in adjacent lake ecosystems.

No abstract

New polyomaviruses are continually being identified, and it is likely that links between this virus family and disease will continue to emerge. Unfortunately, a specific treatment for polyomavirus-associated disease is lacking. Because polyomaviruses express large Tumor Antigen, TAg, we hypothesized that small molecule inhibitors of the essential ATPase activity of TAg would inhibit viral replication. Using a new screening platform, we identified inhibitors of TAg's ATPase activity. Lead compounds were moved into a secondary assay, and ultimately two FDA approved compounds, bithionol and hexachlorophene, were identified as the most potent TAg inhibitors known to date. Both compounds inhibited Simian Virus 40 replication as assessed by plaque assay and quantitative PCR. Moreover, these compounds inhibited BK virus, which causes BKV Associated Nephropathy. In neither case was host cell viability compromised at these concentrations. Our data indicate that directed screening for TAg inhibitors is a viable method to identify polyomavirus inhibitors, and that bithionol and hexachlorophene represent lead compounds that may be further modified and/or ultimately used to combat diseases associated with polyomavirus infection.