Chizu Nakamoto

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.

Highly potent human parathyroid hormone analogs

There is growing evidence showing that intermittent administration of human parathyroid hormone, hPTH(l-84), or its N-terminal fragment hPTH(l-34) can effectively build bone in animals and humans [1]. In an effort to develop a novel bone anabolic agent for the treatment of osteoporosis, we are involved in a search for more potent hPTH(l-34) analogs. NMR studies have indicated that in aqueous solution the major conformational features of hPTH(l-34) include two amphiphilic located at the Nand C-termini connected by a defined reverse turn region [2,3]. Our research was mainly focused on modification of residues in the hydrophobic face of the N-terminal amphiphilic in the reverse turn and at the beginning of the C-terminal