Yeelana Shen

A Novel Growth Hormone Secretagogue-1a Receptor Antagonist That Blocks Ghrelin-Induced Growth Hormone Secretion but Induces Increased Body Weight Gain

Ghrelin, the natural ligand for the growth hormone secretagogue-1a (GHS-1a) receptor, has received a great deal of attention due to its ability to stimulate weight gain and the hope that an antagonist of the GHS-1a receptor could be a treatment for obesity. We have discovered an analog of full-length human ghrelin, BIM-28163, which fully antagonizes GHS-1a by binding to but not activating the receptor. We further demonstrate that BIM-28163 blocks ghrelin activation of the GHS-1a receptor, and inhibits ghrelin-induced GH secretion in vivo. Unexpectedly, however, BIM-28163 acts as an agonist with regard to stimulating weight gain. These results may suggest the presence of an unknown ghrelin receptor that modulates ghrelin actions on weight gain. In keeping with our results on growth hormone (GH) secretion, BIM-28163 acts as an antagonist of ghrelin-induced Fos protein immunoreactivity (Fos-IR) in the medial arcuate nucleus, an area involved in the ghrelin modulation of GH secretion. However, in the dorsal medial hypothalamus (DMH), a region associated with regulation of food intake, both ghrelin and BIM-28163 act as agonists to upregulate Fos-IR. The observation that ghrelin and BIM-28163 have different efficacies in inducing Fos-IR in the DMH, and that concomitant administration of ghrelin and an excess of BIM-28163 results in the same level of Fos-IR as BIM-28163 administered alone may demonstrate that in the DMH both ghrelin and BIM-28163 act via the same receptor. If so, it is unlikely that this receptor is GHS-1a. Collectively, our findings suggest that the action of ghrelin to stimulate increased weight gain may be mediated by a novel receptor other than GHS-1a, and further imply that GHS-1a may not be the appropriate target for anti-obesity strategies.

Discovery and characterization of taspoglutide, a novel analogue of human glucagon-like peptide-1, engineered for sustained therapeutic activity in type 2 diabetes

Aim: Glucagon‐like peptide‐1 (GLP‐1) receptor agonists for the treatment of type 2 diabetes are administered by daily injection because of short plasma half‐lives, which result partly from the biochemical instability of these peptides. There is a medical need for GLP‐1 analogues that can be administered less frequently for patient convenience.

Highly Potent Analogs of Human Parathyroid Hormone and Human Parathyroid Hormone-Related Protein

It is well established that intermittently administered human parathyroid hormone, hPTH(1–84), and its fragment hPTH(1–34) effectively increase bone mass in animals and humans. Because of its unique bone anabolic effect, PTH is considered a potential therapeutic agent for the treatment of osteoporosis. However, the native hPTH(l-84) and its fragment hPTH(l-34) have a relatively narrow therapeutic index, above which they can cause bone resorption and hypercalcemia. To address this problem, we have designed and identified novel PTH/PTHrP analogs that have a wider therapeutic index.

Glucagon-Like Peptide-1 Analogs with Significantly Improved in vivo Activity

Glucagon-like peptide-1 (GLP-1), a potent and strictly glucose-dependent insulino-tropic agent, has received increasing attention as a possible new treatment for type 2 diabetes. Although its effectiveness in type 2 diabetes patients has been demonstrated in clinical evaluations, the potential use of the native GLP-1 as a therapeutic agent is greatly hampered by its short plasma half-life. Physiologically, GLP-1 is rapidly degraded by endoproteases. Here we report that a series of novel human GLP-1 (hGLP-1) analogs have been designed and synthesized, which have greatly improved plasma half-life and significantly enhanced in vivo activity.