Design and development of therapeutic drugs for intractable diseases based on molecular recognition of aspartic proteases

基于天冬氨酸蛋白酶分子识别的疑难杂症治疗药物的设计与开发

• 批准号: 15390039
• 负责人: KISO Yoshiaki
• 金额: $ 7.04万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390039/
• 关键词: enzyme inhibitors; aspartic protease; Alzheimer's disease; β-secretase; plasmepsin; adult T-cell leukemia; HTLV-1 protease; セクレターゼ; HIVプロテアーゼ; マラリア; 分子認識; ドラッグデザイン; 難病治療薬

Based on the substrate transition state concept, we designed and synthesized inhibitors of HIV protease that belongs to aspartic protease. We found an innovative hydroxymethylcarbonyl (HMC) isostere as an ideal transition state mimic and succeeded molecular size reduction. These small-sized HIV protease inhibitors are expected as the next generation anti-HIV drugs. HIV protease inhibitors gained epoch-making success but there are many problems left to be solved such as necessity of high dose, side effects, drug resistance.We aimed to develop low-dose anti-HIV drugs with high tissue translocation ability by designing dipeptide-type HIV protease inhibitors containing the ideal transition state mimic, HMC isostere based on the analysis of interaction between the protease and inhibitors. Furthermore, the dipeptide-type small-sized HIV protease inhibitors exhibited effectiveness against drug-resistant virus and different mutation patterns, and thus have a potential to overcome the drug resistance and side effects. Based on the molecular recognition between mutant protease and inhibitors, we designed dipeptide-type HIV protease inhibitors and synthesized their water-soluble prodrugs as well.We applied this useful methodology for design and synthesis of aspartic protease inhibitors to various important proteases such as plasmepsins that play important role in malaria protozoa proliferation, β-secretase that regulates formation of β-peptide and is probably involved in Alzheimer's disease pathology, and HTLV-1 protease that causes adult T-cell leukemia. These inhibitors are expected to be useful in development of therapeutic drugs for intractable diseases.

基于底物过渡态概念，我们设计并合成了属于天冬氨酸蛋白酶的HIV蛋白酶抑制剂。我们发现了一种创新的羟甲基羰基（HMC）等异构体作为理想的过渡态模拟物，并成功地缩小了分子大小。这些小型HIV蛋白酶抑制剂有望成为新一代抗HIV药物。HIV蛋白酶抑制剂取得了划时代的成功，但仍存在大剂量必要性、副作用、耐药等问题。本研究在分析蛋白酶与抑制剂相互作用的基础上，设计了含有理想过渡态模拟物HMC异位体的二肽型HIV蛋白酶抑制剂，旨在开发具有高组织易位能力的低剂量抗HIV药物。此外，二肽型小尺寸HIV蛋白酶抑制剂对耐药病毒和不同的突变模式表现出有效性，从而具有克服耐药和副作用的潜力。基于突变体蛋白酶与抑制剂之间的分子识别，我们设计了二肽型HIV蛋白酶抑制剂，并合成了其水溶性前药。我们将这种有用的方法应用于设计和合成各种重要蛋白酶的天冬氨酸蛋白酶抑制剂，如在疟疾原生动物增殖中起重要作用的plasmepsins，调节β肽形成并可能参与阿尔茨海默病病理的β分泌酶，以及导致成人t细胞白血病的HTLV-1蛋白酶。这些抑制剂有望用于开发治疗顽固性疾病的药物。

项目成果

Yoshio Hamada: "Water-soluble prodrugs of dipeptide HIV protease inhibitors based on O-N intramolelcular acyl migration : design, synthesis and kinetic study"Bioorganic Medicinal Chemistry. 12(1). 159-170 (2004)

Yoshio Hamada：“基于O-N分子内酰基迁移的二肽HIV蛋白酶抑制剂的水溶性前药：设计、合成和动力学研究”生物有机药物化学。

第19回大学と科学公開シンポジウム講演収録集:アルツハイマー病:治療の可能性を探る

第十九届大学与科学公开研讨会讲座集：阿尔茨海默病：探索治疗的可能性

• 发表时间: 2005
• 作者: Masashi Asai;Chinatsu Hattori;Nobuhisa Iwata;Takaomi C. Saido;Noboru Sasagawa;Beata Szabo;Yasuhiro Hasimoto;Kei Maruyama;Sei-ichi Tamura;Yoshiaki Kiso;Shoichi Ishiura;Aiko Kiso;Y. Kiso;木曽 良明
• 通讯作者: 木曽 良明

Azin Nezami: "High affinity inhibition of a family of Plasmodium falciparum proteases by a designed adaptive inhibitor"Biochemistry. 42(28). 8459-8464 (2003)

Azin Nezami：“设计的适应性抑制剂对恶​​性疟原虫蛋白酶家族的高亲和力抑制”生物化学。

The novel β-secretase inhibitor KMI-429 reduces amyloid β peptide production in amyloid precursor protein transgenic and wild-type mice

• DOI: 10.1111/j.1471-4159.2005.03576.x
• 发表时间: 2006-01-01
• 期刊: JOURNAL OF NEUROCHEMISTRY
• 影响因子: 4.7
• 作者: Asai, M;Hattori, C;Ishiura, S
• 通讯作者: Ishiura, S

Adaptive space search:Design of peptidomimetic inhibitors and prodrugs of aspartic proteases targeting intractable diseases

自适应空间搜索：针对疑难杂症的拟肽抑制剂和天冬氨酸蛋白酶前药的设计

• 发表时间: 2005
• 作者: Masashi Asai;Chinatsu Hattori;Nobuhisa Iwata;Takaomi C. Saido;Noboru Sasagawa;Beata Szabo;Yasuhiro Hasimoto;Kei Maruyama;Sei-ichi Tamura;Yoshiaki Kiso;Shoichi Ishiura;Aiko Kiso;Y. Kiso
• 通讯作者: Y. Kiso