Glucosepane Crosslinks and Undoing Age-Related Tissue Damage

Photo by Erin Ashford
Photo by Erin Ashford

Yale University

Principal Investigator: David Spiegel
Research Team: Prof. Jason Crawford, Nam Kim, Venkata Sabbasani, Matthew Streeter

The long-lived collagen proteins that give structure to our arteries and other tissues are continuously exposed to blood sugar and other highly reactive molecules necessary for life. Occasionally, these sugar molecules will bind to tissue collagen by sheer chemistry, and if not quickly reversed these initial links will in turn bind adjacent strands of collagen, reducing the range of motion of the tissue like the legs of runners in a three-legged race. As a result, these tissues slowly stiffen with age, leading to rising systolic blood pressure, kidney damage, and increased risk of stroke and other damage to the brain.

It is currently thought that the single most common of these Advanced Glycation End-products (AGE) crosslinks is a molecule called glucosepane. A rejuvenation biotechnology that could cleave glucosepane crosslinks would allow bound arterial proteins to move freely again, maintaining and restoring the elasticity of the vessels and preventing the terrible effects of their age-related stiffening. SRF has provided funding to the Yale GlycoSENS group for several years now, in order to develop tools necessary for enabling the development of glucosepane-cleaving drugs.

Research Highlights:

The Yale group’s first major milestone – the first complete synthesis of glucosepane itself – was a sufficient tour de force to earn publication in the prestigious journal Science. In 2018, they were able to scale up this pilot-level method to produce glucosepane in quantities useful for industrial production, and also to synthesize three conformational variants (diastereomers) of glucosepane that may occur in vivo. They are now working on two more such variants. They have also used their synthetic glucosepane to develop glucosepane-targeting antibodies capable of labeling glucosepane in aging tissues, which they are now working up into a monoclonal antibody for mass production that will be compatible with human metabolism and will allow researchers to track the effects of potential glucosepane-cleaving drugs.

Finally, and most excitingly, they have now identified a lead candidate glucosepane-cleaving biocatalyst, and completed the evaluation of seven significant variants and their AGE-breaking mechanism. Today, work continues on synthesizing pentosinane (another common AGE crosslink) and additionally on the AGE-related compounds iso-imidazole and 2-aminoimidazole.

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