Anthrax LF Inhibitor Drug Based On Organosilanes

基于有机硅烷的炭疽 LF 抑制剂药物

• 批准号: 6561946
• 负责人: Scott McNeill Sieburth
• 金额: $ 21.31万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561946
• 关键词: Bacillus anthracis; anthrax; antibacterial agents; chemical substitution; computer simulation; drug design /synthesis /production; hydrolysis; metalloendopeptidases; mitogen activated protein kinase; peptide library; pharmacokinetics; protease inhibitor; silanes

DESCRIPTION (provided by applicant): Silanediols are novel transition-state analog protease inhibitors pioneered in the Principal Investigator's laboratory. These structures are effective inhibitors of metalloprotease enzymes at low nanomolar (nM) levels and can cross cell membranes at rates comparable to non-silane (commercial) pharmaceuticals. B. anthracis LF is a metalloprotease and the source of anthrax toxicity. No effective inhibitor of this enzyme has been described. The initial phase of this research will produce a silanediol inhibitor of LF using known substrate specificities. The second phase will structurally alter this inhibitor to remove the peptide character and thereby improve pharmacokinetic properties. Structural fine-tuning will then yield a clinical candidate for victims of systemic anthrax infection who cannot be saved by antibiotics. -Pro-VaI-Leu-Pro-Ala-Leu-Thr- LF substrate Phase 2 and site of cleavage

描述（由申请人提供）：硅二醇是由首席研究员实验室首创的新型过渡态类似蛋白酶抑制剂。这些结构在低纳摩尔（nM）水平下是金属蛋白酶的有效抑制剂，并且可以以与非硅烷（商业）药物相当的速度穿过细胞膜。LF是一种金属蛋白酶，也是炭疽毒性的来源。目前还没有发现这种酶的有效抑制剂。本研究的初始阶段将利用已知的底物特异性生产一种硅二醇LF抑制剂。第二阶段将在结构上改变该抑制剂以去除肽特征，从而改善药代动力学特性。然后，结构微调将产生一种临床候选者，用于治疗无法通过抗生素拯救的全身性炭疽感染受害者。