Breakthrough Article in Nature Substantiates Thermalin’s New Insulins
An article has been published in the journal Nature that provides a rationale for the unique and advantageous activity of several of the insulin analogs under development at Thermalin.
Jan. 23, 2013 - PRLog -- Thermalin rapid-acting insulins hinge on B-Chain position B24
Cleveland, OH and Boston, MA – January 23, 2013 – An article has been published in the journal Nature that provides a rationale for the unique and advantageous activity of several of the insulin analogs under development at Thermalin (http://www.thermalin.com).
The article, co-authored by Thermalin founder and Chief Science Officer Michael Weiss in an international collaboration, reported a breakthrough in the understanding of how insulin interacts with the insulin receptor on cell surface membranes.
Long an important scientific mystery, scientists have tried for dozens of years to figure out how insulin and related growth factors fit into the insulin receptor “keyhole” to enable uptake of glucose into cells and prevent the hyperglycemia associated with diabetes. For the first time, 90 years after the discovery of insulin, researchers have captured the structural image of the interaction of insulin with its primary binding site on the insulin receptor. The article reveals important details of the interaction and their implications for how the insulin signal is transmitted.
According to Dr. Weiss, “the research has provided insight into the molecular functioning of the insulin receptor and its homolog, the type 1 insulin-like growth factor receptor, which is implicated in tumor growth. This understanding has direct relevance to the structural bases of improved insulin analogues.”
The research utilized recent advances in X-ray protein crystallography to analyze co-crystals of human insulin with the relevant parts of the insulin receptor. It provided new insights into where and how insulin binds to the upside-down-
Insulin is a globular protein made up of two amino acid strings (a 21-residue “A” chain and a 30-residue “B” chain) joined by disulfide bonds. When insulin is stored in the body or in a liquid pharmaceutical formulation, individual insulin molecules typically form into groups of six (“hexamers”)
All rapid-acting insulin analogs on the market today (Humalog®,Novolog®
binding to the receptor. Dr. Weiss had previously discovered that by making more subtle changes at B24, it was possible to further accelerate dimer disassembly with little or no effects on potency. The work published in Nature today suggests that the amino acid at B24 plays a pivotal role in how insulin interacts with the receptor but the precise role of this residue was not clearly visualized in the structure.
“What is clear is that the ability of the hormone to bind to and trigger the receptor requires a switch at this site. Accordingly, we believe that future improvements in rapid-acting insulins will hinge on this important location,” said Bruce Frank, Ph.D., Vice President of Insulin Development at Thermalin and co-inventor of Humalog.
“We are thrilled that the work of Dr. Weiss and his collaborators has received the distinction of being published in Nature,” said Thermalin CEO, Rick Berenson. “At Thermalin we see every day how Mike Weiss’s deep understanding of the insulin protein can guide the creation of unique and improved insulin analogues. It was fascinating to see how many of his intuitions, which pre-dated the work reported in Nature, were consistent with how the insulin receptor actually operates. Now armed with these new insights, I look forward to even more opportunities to engineer better forms of insulin.”
“While there is still a great deal of work to be done and much more to be learned about this incredibly elegant system, the ongoing work of my Australian, American, British, and Czech colleagues offers hope for continued improvements in our understanding with important implications for improving treatments for diabetes patients. I feel privileged for the opportunity to continue to work with these gifted scientists who have dedicated years and decades to this effort,” Dr. Weiss said.
About Thermalin Diabetes
Thermalin was founded to discover and develop novel insulin analogues that are safer, more effective, and enable new devices (such as an artificial pancreas pump), all with the goal of improving the lives of diabetes patients. Based in Cleveland, OH, Thermalin has been supported by $12.4 million in NIH grants and equity investment. The company expects to test its first analogue in humans by the end of 2013.
About Dr. Michael Weiss
Dr. Weiss is Professor and Chairman of Biochemistry at Case Western Reserve University School of Medicine. Mike has more than 150 publications, including four on his insulin analog designs that were named “Paper of the Week” by the Journal of Biological Chemistry. Mike just completed a 5 year term as chair of the NIDDK’s Board of Scientific Councilors. He earned an AB, summa cum laude in Physics in 1978, an MD, summa cum laude, in 1985, and a PhD in biophysics in 1986, all from Harvard.