The new process synthesizes glucosepane, which is considered a critical chemical link in both diabetes and aging. It is also an independent risk factor for long-term microvascular complications in diabetes.
In a study published this week in the journal Science, senior author David Spiegel and his colleagues describe the new synthesis, as well as a new synthetic methodology, which may have applications beyond the current research.
“Glucosepane forms in all human beings during the aging process, and also forms during various diseases, including diabetes,” said Spiegel, a professor of chemistry and pharmacology at Yale. “It is unknown what role glucosepane might play in aging and in these diseases, but several hypotheses have been proposed. With access to synthetic glucosepane, we will now be able to generate tools to examine the role this molecule plays in human health and also, perhaps, develop molecules to inhibit or reverse its formation.”
Until now, it has been difficult to study glucosepane effectively. There is a scarcity of chemically homogeneous glucosepane available for scientists to examine — due to its unusual structure and properties — and researchers have been forced to rely on time-consuming extraction protocols to obtain usable material.
Glucosepane contains a rare isomer of imidazole, which has never before been observed in natural molecules, other than those in the glucosepane family. Spiegel and his colleagues developed a new methodology for synthesizing this imidazole form. The process requires only eight steps.
In an accompanying article in Science, Dale L. Boger of the Scripps Research Institute wrote that the Yale study represents “an important, yet largely underexplored, frontier for chemistry with broad implications in human health.” Boger said Spiegel’s methodology “is important in its own right and will find applications well beyond that envisioned by the authors.”
The first author of the study is Cristian Draghici, a former postdoctoral researcher at Yale who is now at the Broad Institute of MIT and Harvard. Tina Wang, a former Ph.D student at Yale who is now at Harvard, is the other co-author.
The work was supported by the SENS Research Foundation, a non-profit organization devoted to research and treatment of age-related disease that emphasizes a damage repair approach to the diseases of aging.
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