Exploring drug target peptides utilizing in silico analysis

• Project/Area Number: 19209026
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General internal medicine (including Psychosomatic medicine)
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: HIRATA Yukio Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 教授 (50135787)
• Co-Investigator(Kenkyū-buntansha): SHICHIRI Masayoshi 東京医科歯科大学, 医学部附属病院, 准教授 (10206097)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥50,440,000 (Direct Cost: ¥38,800,000、Indirect Cost: ¥11,640,000); Fiscal Year 2008: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000); Fiscal Year 2007: ¥26,390,000 (Direct Cost: ¥20,300,000、Indirect Cost: ¥6,090,000)
• Keywords: バイオインフォマティクス / ペプチドライブラリー / in silico / 生理活性ペプチド / ペプチド創薬 / ペプチド性ホルモン / 機能解析

Research Abstract

ヒトゲノム・cDNA資源データベースをバイオインフォマティクス解析して得られた情報をもとに数多くのペプチドを合成し、ペプチド創薬の観点から有用と推測されるものに焦点を絞って重点的に機能解析することによって生理活性因子候補因子からなるペプチドライブラリーを得た。ユニークな機能を有するいくつもの内因性ペプチド性リガンドを見出しつつあり、それらのヒト体液中での正確な分子存在様式を確認することと併行して、哺乳動物主要臓器における受容体の分布や生体内作用などを検討し、さらに物理化学的特性も含めて広範な解析を行った。我々の開発したこの新規ペプチド探索法は、従来の手法では発見できなかった内因性ペプチドホルモンを発見するには特に有効な手段であることが考えられた。

Research Products

• [Journal Article] Release of salusin-β from human monocytes/macrophages (2010)
  • Author(s): Sato K, Fujimoto K, Koyama T, Shichiri M
  • Journal Title: Reg Peptides 162 Pages: 68-72
• [Journal Article] Serum levels and urinary excretion of salusin-α in renal insufficiency (2010)
  • Author(s): Kimoto S, Sato K, Watanabe T, Suguro T, Koyama T, Shichiri M
  • Journal Title: Reg Peptides 162 Pages: 129-32
• [Journal Article] Expression of prosalusin in human neuroblastoma cells (2009)
  • Author(s): Nakayama C, Shichiri M, Sato K, Hirata Y
  • Journal Title: Peptides 30 Pages: 1362-7
• [Journal Article] Rifampicin as an oral angiogenesis inhibitor targeting hepatic cancers (2009)
  • Author(s): Shichiri M, Fukai N, Kono Y, Tanaka Y
  • Journal Title: Cancer Res 69 Pages: 4760-8
• [Journal Article] Presence of immunoreactive salusin-β in human plasma and urine (2009)
  • Author(s): Sato K, Sato T, Susumu T, Koyama T, Shichiri M
  • Journal Title: Reg Peptides 158 Pages: 63-7
• [Journal Article] Nitric oxide upregulates dimethylarginine dimethylaminohydrolase-2 via cyclic GMP induction in endothelial cells (2008)
  • Author(s): Sakurada M, Shichiri M, Imamura M, Azuma H, Hirata Y
  • Journal Title: Hypertension 52 Pages: 903-9
• [Journal Article] Aldosterone induces superoxide generation via Rac1 activation in endothelial cells (2008)
  • Author(s): Iwashima F, Yoshimoto T, Minami I, Sakurada M, Hirono Y, Hirata Y
  • Journal Title: Endocrinology 149 Pages: 1009-14
• [Journal Article] Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages (2008)
  • Author(s): Miyake A, Murata Y, Okazawa H, Ikeda H, Niwayama Y, Ohnishi H, Hirata Y, Matozaki T
  • Journal Title: Genes to Cells 13 Pages: 209-19
• [Journal Article] Aldosterone-stimulated SGK1 activity mediates profibrotic signaling in the mesangium (2008)
  • Author(s): Terada Y, Kuwana H, Kobayashi T, Okado T, Suzuki N, Yoshimoto T, Hirata Y, Sasaki S
  • Journal Title: J Am Soc Nephrol 19 Pages: 298-309
• [Journal Article] Chronic osmotic stimuli increase salusin-β-like immunoreactivity in the rat hypothalamo-neurohypophyseal system : possible involvement of salusin-β on [Ca^<2+>]_i increase and neurohypophyseal hormone release from the axon terminals (2008)
  • Author(s): Saito T, Dayanithi G, Saito J, Onaka T, Urabe T, Watanabe TX, Hashimoto H, Yokoyama T, Fujihara H, Yokota A, Nishizawa S, Hirata Y, Ueta Y
  • Journal Title: J Neuroendocrinol 20 Pages: 207-19
• [Journal Article] Biosynthesis and secretion of salusin-α from human cells (2008)
  • Author(s): Sato K, Koyama T, Shichiri M
  • Journal Title: Peptides 29 Pages: 2203-7
• [Journal Article] Serum salusin-α levels are decreased and correlated negatively with carotid atherosclerosis in essential hypertensive patients (2008)
  • Author(s): Watanabe T, Suguro T, Sato K, Koyama T, Nagashima M, Kodate S, Hirano T, Adachi M, Shichiri M, Miyazaki A
  • Journal Title: Hypertens Res 31 Pages: 463-8
  • NAID: 10021933748
• [Journal Article] Impact of salusin-α and-β on human macrophage foam cell formation and coronary atherosclerosis (2008)
  • Author(s): Watanabe T, Nishio K, Kanome T, Matsuyama TA, Koba S, Sakai T, Sato K, Hongo S, Nose K, Ota H, Kobayashi Y, Katagiri T, Shichiri M, Miyazaki A
  • Journal Title: Circulation 117 Pages: 638-48
• [Journal Article] Biosynthesis and secretion of salusin-<from human cells (2008)
  • Author(s): Sato K, Koyama T, Shichiri M
  • Journal Title: Peptides 29 Pages: 2203-2207
  • Peer Reviewed
• [Journal Article] Serum salusin-<levels are decreased and correlated negatively with carotid atherosclerosis in essential hypertensive patients (2008)
  • Author(s): Watanabe T, et al.
  • Journal Title: Hypertens Res 31 Pages: 463-468
  • Peer Reviewed
• [Journal Article] Impact of salusin-<and -(R)on human macrophage foam cell formation and coronary atherosclerosis (2008)
  • Author(s): Watanabe T, et al.
  • Journal Title: Circulation 29 Pages: 2203-2207
  • Peer Reviewed
• [Journal Article] Chronic osmotic stimuli increase salusin-β-like immunoreactivity in the rat hypothalamo- neurohypophyseal system : possible involvement of alusin-β on [Ca^<2+>]i increase and neurohypophyseal hormone release from the axon terminals (2008)
  • Author(s): Saito T, et al.
  • Journal Title: J Neuroendocrinol 20 Pages: 207-219
  • Peer Reviewed
• [Journal Article] Aldosterone induces superoxide generation via Racl activation in endot helial cells (2008)
  • Author(s): Iwashima F, et al.
  • Journal Title: Endocrinology 149 Pages: 1009-1014
  • Peer Reviewed
• [Journal Article] NO upregulates dimethylarginine dimethylaminohydrolase-2 via cGMP induction in endothelial cells (2008)
  • Author(s): Sakurada M, Shichiri M, Imamura M, Azuma H, Hirata Y
  • Journal Title: Hypertension 52 Pages: 903-909
  • Peer Reviewed
• [Journal Article] Expression of prosalusin in human neuroblastoma cells (2008)
  • Author(s): Nakayama C, et al
  • Journal Title: Peptides 30 Pages: 1362-1367
  • Peer Reviewed
• [Journal Article] Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension : the possible role of local renin-angiotensin system (2007)
  • Author(s): Hirono Y, Yoshimoto T, Suzuki N, Sugiyama T, Sakurada M, Takai S, Kobayashi N, Shichiri M, Hirata Y
  • Journal Title: Endocrinology 148 Pages: 1688-96
• [Journal Article] Systemic distribution of salusin expression in the rats (2007)
  • Author(s): Suzuki N, Shichiri M, Akashi T, Sato K, Sakurada M, Hirono Y, Yoshimoto T, Koyama T, Hirata Y
  • Journal Title: Hypertens Res 30 Pages: 1255-62
  • NAID: 10021260743
• [Journal Article] Reply to 'Salusins ; newly identified bioactive peptides with hemodynamic and mitogenic activities' (2007)
  • Author(s): Shichiri M
  • Journal Title: Nature Med 13 Pages: 661-2
• [Journal Article] Defective expression of prohormone convertase 1/3 in silent corticotroph adenoma (2007)
  • Author(s): Tateno T, Izumiyama H, Doi M, Akashi T, Ohno K, Hirata Y
  • Journal Title: Endocrine J 54 Pages: 777-82
  • NAID: 10020093046
• [Journal Article] Differential gene expression in adrenocorticotropin (ACTH)-secreting and non-functioning pituitary tumors (2007)
  • Author(s): Tateno T, Izumiyama H, Doi M, Yoshimoto T, Shichiri M, Inosita M, Oyama K, Yamada S, Hirata Y
  • Journal Title: Eur J Endocrinol 157 Pages: 717-24
• [Journal Article] Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high-fat-induced obese mice (2007)
  • Author(s): Tsuchiya K, Sakai H, Suzuki N, Iwashima F, Yoshimoto T, Shichiri M, Hirata Y
  • Journal Title: Endocrinology 148 Pages: 4548-56
• [Journal Article] Aldosterone as a cardiovascular risk hormone (2007)
  • Author(s): Yoshimoto T, Hirata Y
  • Journal Title: Endocrine J 54 Pages: 359-70
  • NAID: 130004770030
• [Journal Article] MARCH-X1, a novel transmembrane ubiquitin ligase implicated in ubiquitin-dependent protein sorting in developing spermatids (2007)
  • Author(s): Morokuma Y, Nakamura N, Kato A, Notoya M, Yamamoto Y, Sakai Y, Fukuda H, Yamashina S, Hirata Y, Hirose S
  • Journal Title: J Biol Chem 282 Pages: 24806-15
• [Journal Article] Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension : The possible role of local renin-angiotensin system (2007)
  • Author(s): Hirono Y, et al.
  • Journal Title: Endocrinology 148 Pages: 1688-1696
  • Peer Reviewed
• [Journal Article] Reply to 'Salusins ; newly identified bioactive peptides with hemodynamic and mitogenic activities' (2007)
  • Author(s): Shichiri M
  • Journal Title: Nature Medicine 13 Pages: 661-662
  • Peer Reviewed
• [Journal Article] Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high-fat-induced obese mice (2007)
  • Author(s): Tsuchiya K, et al.
  • Journal Title: Endocrinology 148 Pages: 4548-4556
  • Peer Reviewed
• [Journal Article] Systemic distribution of salusin expression in the rat (2007)
  • Author(s): Suzuki N, et al.
  • Journal Title: Hypertension Research 30 Pages: 1255-1262
  • Peer Reviewed
• [Presentation] NO upregulates dimethylarginine dimethylaminohydrolase-2 via cGMP induction in endothelial cells (2008)
  • Author(s): Sakurada M, Shichiri M, Imamura M, Azuma H, Hirata Y
  • Organizer: The 22th Scientific Meeting of the International Society of Hypertension
  • Place of Presentation: Berlin, Germany
• [Presentation] Defective expression of prohormone convertase 4 in pleural solitary fibrous tumor causing non-islet cell tumor hypoglycemia (NICTH) (2008)
  • Author(s): Tani Y, Tateno T, Izumiyama H, Doi M, Yoshimoto T, Hirata Y
  • Organizer: The Endocrine Society Annual Meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] Metabolic syndrome is associated with endothelial dysfunction : Important roles of hyperinsulinemia and Hypertension (2008)
  • Author(s): Tsuchiya K, Nakayama C, Iwashima F, Sakai H, Yoshimoto T, Hirata Y
  • Organizer: The Endocrine Society Annual Meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] Differential gene expression of somatostatin receptor (SSTR) subtype and dopamine type 2 receptor (D2R) in adrenocorticotropin (ACTH)-secreting and non-functioning pituitary tumors (2008)
  • Author(s): Tateno T, Izumiyama H, Doi M, Yoshimoto T, Oyama K, Yamada Y, Hirata Y
  • Organizer: The Endocrine Society's Annual Meeting
  • Place of Presentation: San Francisco, USA
• [Presentation] ヒト神経芽細胞腫におけるサリューシン-αの発現 (2008)
  • Author(s): 中山千里、佐藤健吾、吉本貴宣、七里眞義、平田結喜緒
  • Organizer: 第12回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 熊本
• [Presentation] ラットにおけるサリューシン-αおよびβの組織分布 (2008)
  • Author(s): 鈴木紀子、中野妙、中山千里、吉本貴宣、七里眞義、平田結喜緒
  • Organizer: 第12回日本心血管内分泌代謝学会学術総会
  • Place of Presentation: 熊本
• [Presentation] In silico 探索法による循環調節因子サリューシンの発見と新たな展開 (2007)
  • Author(s): 七里眞義
  • Organizer: 第11回日本心血管内分泌代謝学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-11-17
• [Presentation] In silico 探索法による循環調節因子サリューシンの同定と新たな展開 (2007)
  • Author(s): 七里眞義, 平田結喜緒
  • Organizer: 第11回日本心血管内分泌代謝学会 シンポジウム
  • Place of Presentation: 東京
• [Presentation] Possible involvement of small GTP-binding protein, Rac-1, in aldosterone-stimulated superoxide production in endothelial cells (2007)
  • Author(s): Iwashima F, Yoshimoto T, Sakurada M, Minami I, Hirata Y
  • Organizer: The Endocrine Society Annual Meeting
  • Place of Presentation: Toronto, Canada
• [Presentation] Differential gene expression in adrenocorticotropin (ACTH)-secreting and non-functionong pituitary tumors (2007)
  • Author(s): Tateno T, Izumiyama H, Doi M, Yoshimoto T, Oyama K, Yamada S, Hirata Y
  • Organizer: The Endocrine Society Annual Meeting
  • Place of Presentation: Toronto, Canada
• [Presentation] Endothelial dysfunction in patients with Cushing's syndrome and acromegaly (2007)
  • Author(s): Tsuchiya K, Yoshimoto T, Nakayama C, Iwashima F, Sakai H, Hirata Y
  • Organizer: The Endocrine Society Annual Meeting
  • Place of Presentation: Toronto, Canada
• [Presentation] Effects of telmisartan on endothelial function and arterial stiffness in diabetic patients with hypertension (2007)
  • Author(s): Wago T, Tsuchiya K, Kouyama R, Izumiyama H, Doi M, Yoshimoto T, Hirata Y
  • Organizer: The 17th European Meeting on Hypertension
  • Place of Presentation: Milano, Italy
• [Book] 「In silico ペプチド探索」遺伝子医学MOOK第8号「ペプチドと創薬」(寒川賢治, 南野直人, 編) (2007)
  • Author(s): 七里眞義
  • Publisher: メディカルドウ
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/cme/research/index.html
• [Patent(Industrial Property Rights)] 特許権 (2009)
  • Inventor(s): 七里眞義 鈴木淳一
  • Industrial Property Rights Holder: 東京医科歯科大学・(株)プロテインエクスプレス
  • Industrial Property Number: 2009-064588
  • Filing Date: 2009-03-17
• [Patent(Industrial Property Rights)] 特許権 (2008)
  • Inventor(s): 七里眞義
  • Industrial Property Rights Holder: 東京医科歯科大学・(株)プロテインエクスプレス
  • Filing Date: 2008-10-24
• [Patent(Industrial Property Rights)] 特許 (2007)
  • Inventor(s): 渡部琢也, 七里眞義
  • Industrial Property Rights Holder: 昭和大学・東京医科歯科大学・(株)プロテインエクスプレス
  • Industrial Property Number: 2007-127131
  • Filing Date: 2007-05-11
• [Patent(Industrial Property Rights)] サリューシンをターゲットとする動脈硬化性疾患の治療剤及び検出薬
  • Industrial Property Number: 2007-127131
• [Patent(Industrial Property Rights)] サリューシン-βを含む医薬
  • Industrial Property Number: 2007-279006
• [Patent(Industrial Property Rights)] サリューシン-βのアンタゴニストを含む心筋虚血再灌流傷害抑制剤法
  • Industrial Property Number: 2009-064588